Aryl-n-aryl derivatives for treating a RNA virus infection

ABSTRACT

A compound: 
                         
wherein X 1  represents an alkenylene group, a —NH—CO— group, a —CO—NH— group, Y 1  represents an aryl group selected from pyridyl, pyrazinyl or pyrimidinyl, X 2  represents —O—, —CO—NH—, —NH—CO—NH—, —OCH 2 —, —NH—CO—, a divalent 5-membered heteroaromatic ring comprising 1 to 4 heteroatoms or —SO 2 —NH—, and Y 2  represents a hydrogen atom, a hydroxyl group, a morpholinyl group, a piperidinyl group, optionally substituted by a (C 1 -C 4 )alkyl group, a piperazinyl group, optionally substituted by a (C 1 -C 4 )alkyl group, or —CR 1 R 2 R 3  or alternatively X 2 —Y 2  represents —CONR c R d , wherein R c  and R d  form, together with the nitrogen atom a heterocyclic ring, optionally substituted by one or two (C 1 -C 4 )alkyl group, by a cyclopentyl group thus forming a spirocyclopentyl, or by a trifluoromethyl group, or any of its pharmaceutically acceptable salt, for use in the treatment and/or prevention of a RNA virus infection caused by a RNA virus belonging to group IV or V of the Baltimore classification.

The present invention relates to compounds useful for preventing and/ortreating a RNA virus infection, and most preferably a RNA virusinfection caused by RNA viruses belonging to group IV or V of theBaltimore classification.

The present invention further relates to some new compounds, inparticular useful for preventing and/or treating a RNA virus infection,and most preferably a RNA virus infection caused by a RNA virusbelonging to group IV or V of the Baltimore classification.

It further relates to the pharmaceutical compositions containing saidnew compounds and to the chemical synthesis processes for obtainingthem.

BACKGROUND

Viruses are one of the major causes of diseases around the world.Viruses are generally defined as small, non-living, infectious agentsthat replicate only within living cells, as they do not possess acompletely autonomous replication mechanism. Although diverse in shapeand size, they typically consist of a virus particle (known as a“virion”), made from a protein coat which comprises at least one nucleicacid molecule and optionally, depending on the type of virus, one ormore proteins or nucleoproteins.

Because viruses do not possess a completely autonomous replicationmechanism, they must necessarily rely on the machinery and metabolism ofthe infected cell or host, in order to replicate and produce multiplecopies of themselves.

Even though their replication cycle varies greatly between species, itis generally recognized that the life cycle of viruses includes sixbasic steps: attachment, penetration, uncoating, replication, assemblyand release.

Depending on the nature of the targeted virus, therapeutic moleculeshave been designed which may interfere with one or more of thosemechanisms.

Among those, the replication step involves not only the multiplicationof the viral genome, but also the synthesis of viral messenger RNA, ofviral protein, and the modulation of the transcription or translationmachinery of the host. However, it is also clear that the type of genome(single-stranded, double-stranded, RNA, DNA . . . ) characterizesdramatically this replication step. For instance, most DNA virusesassemble in the nucleus while most RNA viruses develop solely in thecytoplasm. Also, there is increasing evidence that single-stranded RNAviruses such as Influenza use the host RNA splicing and maturationmachinery.

Accordingly, and considering the implications of a given type of genomein the replication step, the Baltimore classification of viruses wasdeveloped. This classification clusters viruses into families (or“groups”) depending on their type of genome. The present virusclassification, as in 2018, comprises seven different groups:

-   -   Group I: double-stranded DNA viruses (dsDNA);    -   Group II: single-stranded DNA viruses (ssDNA);    -   Group III: double-stranded RNA viruses (dsRNA);    -   Group IV: (+)strand or sense RNA viruses ((+)ssRNA);    -   Group V: (−)strand or antisense RNA viruses ((−)ssRNA);    -   Group VI: single-stranded RNA viruses having DNA intermediates        (ssRNA-RT);    -   Group VII: double-stranded DNA viruses having RNA intermediates        (dsDNA-RT).

According to that classification, viruses belonging to the Group VI arenot, stricto sensu, RNA viruses. For the same reasons, viruses belongingto the Group VII are not, stricto sensu, DNA viruses. One well-studiedexample of a virus family belonging to the Group VI is the familyRetroviridae (retrovirus) which includes HIV. One well-studied exampleof a virus family belonging to the Group VII is the familyHepadnaviridae which includes the Hepatitis B virus (HBV).

As a representative of viruses pertaining to group IV one may cite thePicornaviruses (which is a family of viruses that includes well-knownviruses like Hepatitis A virus, enteroviruses, rhinoviruses, poliovirus,and foot-and-mouth virus), SARS virus, Hepatitis C virus, yellow fevervirus, and rubella virus. The Togaviridae family also pertains to thegroup IV and a known genus thereof is alphavirus, encompassing theChikungunya virus. Flaviridae is also a family pertaining to group IV,encompassing a famous virus transmitted by mosquitoes, i.e. the Denguevirus.

As a representative of viruses pertaining to group V one may cite theFiloviridae virus family encompassing the Ebola virus, theParamyxoviridae family encompassing the Respiratory Syncytial virus(RSV), the Rhabdoviridae family, the Orthomyxoviridae familyencompassing the Influenzavirus A, Influenzavirus B and InfluenzavirusC.

Groups within the virus families particularly focused in the frameworkof the present invention are the ones encompassing RNA viruses,especially single-stranded RNA viruses, and more specifically RNAviruses belonging to group IV and group V of the Baltimoreclassification.

There are few cures for diseases caused by RNA virus infections, inparticular single-stranded RNA viruses, and more specifically RNA virusinfections from viruses belonging to group IV and V of the Baltimoreclassification. Treatment is focused on relieving the symptoms.Therefore, there is still a need to identify new antiviral drugs totreat RNA virus infections, such as RNA virus infection from group IVand V, in particular small chemical molecules.

Definitions

As used herein, the term “patient” refers to either an animal, such as avaluable animal for breeding, company or preservation purposes, orpreferably a human or a human child, which is afflicted with, or has thepotential to be afflicted with, one or more diseases and conditionsdescribed herein.

In particular, as used in the present application, the term “patient”refers to a mammal such as a rodent, cat, dog, primate or human,preferably said subject is a human and also extends to birds.

The identification of those patients who are in need of treatment ofherein-described diseases and conditions is well within the ability andknowledge of one skilled in the art. A veterinarian or a physicianskilled in the art can readily identify, by the use of clinical tests,physical examination, medical/family history or biological anddiagnostic tests, those patients who are in need of such treatment.

In the context of the invention, the term “treating” or “treatment”, asused herein, means reversing, alleviating, inhibiting the progress of,or preventing the disease resulting from RNA virus infection, and moreparticularly RNA virus infection from group IV or V, or one or moresymptoms of such disease.

As used herein, an “effective amount” refers to an amount of a compoundof the present invention which is effective in preventing, reducing,eliminating, treating or controlling the symptoms of theherein-described diseases and conditions, i.e. RNA vims infection, andmore particularly RNA vims infection from group IV or V. The term“controlling” is intended to refer to all processes wherein there may bea slowing, interrupting, arresting, or stopping of the progression ofthe diseases and conditions described herein, but does not necessarilyindicate a total elimination of all disease and condition symptoms, andis intended to include prophylactic treatment.

The term “effective amount” includes “prophylaxis-effective amount” aswell as “treatment-effective amount”.

The term “preventing”, as used herein, means reducing the risk of onsetor slowing the occurrence of a given phenomenon, namely in the presentinvention, a disease resulting from a RNA vims infection, and moreparticularly a RNA vims infection from group IV or V.

As used herein, «preventing» also encompasses «reducing the likelihoodof occurrence» or «reducing the likelihood of reoccurrence».

The term “prophylaxis-effective amount” refers to a concentration ofcompound of this invention that is effective in inhibiting, preventing,decreasing the likelihood of the disease by RNA viruses, and moreparticularly by a RNA vims from group IV or V of the Baltimoreclassification, or preventing the RNA virus infection and in particulara RNA vims infection from group IV or V or preventing the delayed onsetof the disease by the RNA vims, and more particularly by a RNA vims fromgroup IV or V, when administered before infection, i.e. before, duringand/or slightly after the exposure period to the RNA vims, and inparticular to the RNA vims from group IV or V.

Likewise, the term “treatment-effective amount” refers to aconcentration of compound that is effective in treating the RNA vimsinfection, e.g. leads to a reduction in RNA viral infection, followingexamination when administered after infection has occurred.

As used herein, the term “pharmaceutically acceptable” refers to thosecompounds, materials, excipients, compositions or dosage forms whichare, within the scope of sound medical judgment, suitable for contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response or other problem complicationscommensurate with a reasonable benefit/risk ratio.

As used herein, a “viral infection or related condition” refers to aninfection of condition related to a vims, more particularly said vimshaving a RNA genome, and especially a RNA virus belonging to group IV orV according to the Baltimore classification. Viruses may be furtherclassified in distinct families, orders and genus.

For reference, the content of the “Baltimore classification” which isreported herein further references to the virus taxonomy as set forth inthe database of the 2017 International Committee of Taxonomy of Viruses(ICTV) as released online on Mar. 12, 2018 athttp://ictvonline.org/virusTaxonomy.asp. This taxonomy is incorporatedherein in its entirety.

Alphaviruses may in particular be considered by the invention andpertain to the Group IV RNA viruses and the Togaviridae family, whichcan be defined as positive-sense single-stranded RNA viruses or (+)ssRNAviruses. Their order is “Unassigned” according to the Virus Taxonomy of2017. The Togaviridae family includes the Alphavirus and Rubivirusgenus.

Examples of Alphaviruses which are considered by the invention include:Barmah Forest virus, Chikungunya virus, Mayaro virus, O'nyong'nyongvirus, Ross River virus, Semliki Forest virus, Una virus, Eastern equineencephalitis virus, Tonate virus, Venezuelan equine encephalitis virusand Wester equine encephalitis virus.

Most preferably, an alphavirus infection or alphavirus relatedcondition, according to the invention, is a Chikungunya virus infectionor Chikungunya virus-related condition.

More particularly, Chikungunya virus (CHIKV) is a RNA virus whichpertains to the alphavirus genus which in turn belongs to theTogaviridae family, i.e. Group IV from the Baltimore classification.Chikungunya is a mosquito-borne viral disease first described during anoutbreak in southern Tanzania in 1952. CHIKV is an enveloped, positivesense, single-stranded RNA virus with a genome of approximately 12 kbnucleotides long. The genome of CHIKV is organized as follows:5′-cap-nsP1-nsP2-nsP3-nsP4-(junction region)-C-E3-E2-6k-El-poly(A)-3′,in which the first four proteins (nsP1-4) are nonstructural proteins,and the structural proteins are the capsid (C) and the envelope proteins(E). There is no distinct serotypic difference among CHIKV isolated fromAfrica, Asia and the islands of the Indian Ocean. Phylogenetic analysesbased on El gene sequences can group CHIKV into three genotypes(lineages): Asian, cast/central/south African (ECSA), and West African.The Asian genotype differed from the ECSA and West African genotypes bynucleotide levels of −5% and −15%, respectively. The African genotypes(ECSA versus West African) were −15% divergent. The amino acididentities across the three genotypes varied from 95.2 to 99.8%.

Chikungunya virus may cause outbreaks associated with severe morbidity.

Chikungunya is a viral disease transmitted to humans by infectedmosquitoes. Both Ae. aegypti and Ae. albopictus have been implicated inlarge outbreaks of Chikungunya. Whereas Ae. aegypti is confined withinthe tropics and sub-tropics, Ae. albopictus also occurs in temperate andeven cold temperate regions. In recent decades, Ae. albopictus hasspread from Asia to become established in areas of Africa, Europe andthe Americas.

After infection with Chikungunya virus, there is an incubation periodlasting 2-4 days on average, followed by disease symptoms. Among suchsymptoms, fever and severe joint pain may be cited. Other symptomsinclude muscle pain, headache, nausea, back pain, fatigue, myalgia andrash. Severe clinical manifestations of Chikungunya infection can alsooccur, for example, haemorrhagic fever, conjunctivitis, photophobia,hepatitis, stomatitis. Neurologic manifestations such as encephalitis,febrile seizures, meningeal syndrome and acute encephalopathy were alsoreported.

Joint pain is often debilitating and can vary in duration.

The proximity of mosquito breeding sites to human habitation is asignificant risk factor for Chikungunya.

The distribution of Chikungunya virus mainly occurs in Africa, India andSouth Eastern Asia. In recent decades, mosquito vectors of Chikungunyahave spread to Europe and the Americas. In 2007, disease transmissionwas reported for the first time in a localized outbreak in north-easternItaly. Outbreaks have since been recorded in France and Croatia.

Dengue viruses which present various serotypes, may also be consideredby the invention and pertain to the Group IV RNA viruses and theFlaviviridae family, which can be defined as a positive-sensesingle-stranded RNA or (+)ss RNA viruses. More particularly Denguevirus, is a (+)ssRNA virus belonging to group IV of the Baltimoreclassification. It is part of the Flavivirus genus, which belongs to theFlaviviridae family. Other viruses pertaining to the Flaviviridae familyare hepatitis C virus and yellow fever virus.

Viruses of the Mononegavirales order are also particularly considered bythe invention. The order Mononegavirales includes viruses belonging toGroup V of the Baltimore classification. As of 2018, this order includesmainly the following virus families: Bomaviridae, Mymonaviridae,Filoviridae, Nyamiviridae, Pammyxoviridae, Pneumoviridae, Rhabdoviridae,and Sunviridae.

Human respiratory syncytial virus (HRSV) is a syncytial virus thatcauses respiratory tract infections. It is a major cause of lowerrespiratory tract infections and hospital visits during infancy andchildhood. HRSV virus may in particular be considered by the inventionand pertain to the Group V of RNA viruses. More particularly, RSV virusis a (−)ssRNA virus belonging to group V of the Baltimoreclassification. It is a pneumovirus which is part of the Pammyxoviridaefamily, which belongs to the Mononegavirales order. Among other virusesof the Mononegavirales order, those which are particularly considered bythe invention include: measles virus, mumps virus, Nipah virus, rabiesvirus, and human parainfluenza virus (which includes HPIV-1, HPIV-2,HPIV-3 and HPIV-4). Of note, the Paramyxovirinae subfamily wasconventionally merged into the Pammyxoviridae family, by reference tothe taxonomy of the Mononegavirales order updated in 2016.

The virus genus which are particularly considered within thePammyxoviridae family include: Aquapammyxovirus, Avulavirus, Ferlavirus,Henipavirus, Morbillivirus, Respirovirus and Rubulavirus genus.

Viruses of the Orthomyxoviridae family are also particularly consideredby the invention. The Orthomyxoviridae family belongs to an “Unassigned”order according to the 2017 Virus Taxonomy. The virus genus which areparticularly considered within the Orthomyxoviridae family include:Alphainfluenzavirus, Betainfluenzavirus, Deltainfluenzavirus,Gammainfluenzavirus, Isavirus, Quaranjavirus, and Thogotovims.

Influenzavirus A, Influenzavirus B, Influenzavirus C may in particularbe considered by the invention and pertain to the Group V RNA virusesand the Orthomyxoviridae family, which can be defined as anegative-sense single-stranded RNA or (−)ss RNA viruses. Isavirus andThogotovirus also belong to the Orthomyxoviridae order.

DETAILED DESCRIPTION OF THE INVENTION

The inventors have surprisingly found that aryl-N-aryl compounds areendowed with a broad-spectrum activity against RNA viruses, and moreparticularly single-stranded RNA viruses belonging to Group IV or V ofthe Baltimore classification. Groups IV and V include respectively(+)ssRNA viruses and (−)ssRNA viruses; which also refer topositive-sense single-stranded RNA viruses and negative-sensesingle-stranded RNA viruses.

For reference, the content of the «Baltimore classification» isconsidered in light of the Classification and Nomenclature of viruses asset forth in the 10th report on Virus Taxonomy dated 2017.

The present document discloses a compound of formula (I)

-   -   wherein:

ring and

ring independently mean a phenylene or a pyridylene group,

-   -   wherein the group

is in meta or para position on the

ring, m particular m meta position, with respect to the —NH— group,

-   -   X¹ represents an alkenylene group, in particular an ethenylene        group, a —NH—CO— group, a —CO—NH— group, a —CR_(a)R_(b)O— group,    -   Y¹ represents an aryl group selected from a 2-pyridyl group or a        pyrimidinyl group, wherein one of the nitrogen atom of the        pyrimidinyl group is in ortho position with respect to X¹,    -   or alternatively X¹—Y¹ represents a group (A) of formula

-   -   X² represents a —CO—NH— group, a —NH—CO—NH— group, a —OCH₂—        group, a —NH—CO— group or a —SO₂—NH— group,    -   n is 0, 1, 2 or 3,    -   m and m′ are independently 0, 1 or 2,    -   Y² represents a hydrogen atom, a hydroxyl group or a —CR¹R²R³        group, wherein R¹, R² and R³ independently represent a hydrogen        atom, a fluorine atom or a (C₁-C₄)alkyl group, being understood        that no more than one of R¹, R² and R³ is a hydrogen atom, or R¹        and R² form together with the carbon atom bearing them a        (C₃-C₈)cycloalkyl group, said (C₃-C₈)cycloalkyl group being        optionally substituted by one or two (C₁-C₄)alkyl group, halogen        atom or (C₁-C₄)alkoxy group and said (C₃-C₈)cycloalkyl group        being optionally interrupted on said R¹ and/or R² by an oxygen        atom,    -   R and R′ independently represent a halogen atom, a (C₁-C₄)alkyl        group, a (C₃-C₆)cycloalkyl group, a (C₁-C₅)alkoxy group, a        —SO₂—NR_(a)R_(b) group, a —SO₃H group, a —OH group, a        —O—SO₂—OR_(c) group or a —O—P(═O)—(OR_(c))(OR_(d)) group,    -   R_(a), R_(b), R_(c) and R_(d) independently represent a hydrogen        atom or a (C₁-C₄)alkyl group,    -   provided that when X¹ is a —CR_(a)R_(b)O— group, Y¹ may further        be a 3-pyridyl, a 4-pyridyl or a phenyl group optionally        substituted by one or two substituent(s) selected from a halogen        atom, a (C₁-C₄)alkyl group, a cyano group, a (C₁-C₅)alkoxy        group, a trifluoromethyl group, a trifluoromethoxy group, a        —SO₂—NR_(a)R_(b) group, a —SO₃H group, a —OH group, a        —O—SO₂—OR_(c) group or a —O—P(═O)—(OR_(c))(OR_(d)) group,    -   or any of its pharmaceutically acceptable salt,

for use in the treatment and/or prevention of a RNA virus infectioncaused by a RNA virus belonging to group IV or V of the Baltimoreclassification and in particular a Chikungunya viral infection, a Dengueviral infection, an Influenza viral infection or a RSV viral infectionor a virus-related condition.

According to a first aspect, the present invention relates to a compoundof formula (I)

-   -   wherein

ring and

ring independently mean a phenylene or a pyridylene group,

-   -   X¹ represents an alkenylene group, a —NH—CO— group, a —CO—NH—        group,    -   Y¹ represents an aryl group selected from a pyridyl group, a        pyrazinyl group or a pyrimidinyl group,    -   X² represents        -   a —O— group,        -   a —CO—NH— group,        -   a —NH—CO—NH— group,        -   a —OCH₂— group,        -   a —NH—CO— group,        -   a divalent 5-membered heteroaromatic ring comprising 1, 2, 3            or 4 heteroatoms, such as a triazole or an oxadiazole,        -   or        -   a —SO₂—NH— group,    -   n is 0, 1, 2 or 3,    -   m and m′ are independently 0, 1 or 2,    -   Y² represents        -   a hydrogen atom,        -   a hydroxyl group,        -   a morpholinyl group,        -   a piperidinyl group, optionally substituted by a            (C₁-C₄)alkyl group,        -   a piperazinyl group, optionally substituted by a            (C₁-C₄)alkyl group,        -   or        -   a —CR¹R²R³ group, wherein R¹, R² and R³ independently            represent a hydrogen atom, a fluorine atom or a (C₁-C₄)alkyl            group, being understood that no more than one of R¹, R² and            R³ is a hydrogen atom, or R¹ and R² form together with the            carbon atom bearing them a (C₃-C₈)cycloalkyl group, said            (C₃-C₈)cycloalkyl group being optionally substituted by one            or two (C₁-C₄)alkyl group, halogen atom or (C₁-C₄)alkoxy            group and said (C₃-C₈)cycloalkyl group being optionally            interrupted on said R¹ and/or R² by an oxygen atom,

or alternatively X²—Y² represents a group —C(═O)—NR_(c)R_(d), whereinR_(c) and R_(d) form, together with the nitrogen atom a saturatedheterocyclic ring, optionally substituted by one or two (C₁-C₄)alkylgroup, by a cyclopentyl group thus forming a spirocyclopentylderivative, or by a trifluoromethyl group,

-   -   R and R′ independently represent        -   a (C₁-C₄)alkyl group,        -   a (C₃-C₆)cycloalkyl group,        -   a halogen atom,        -   a (C₁-C₅)alkoxy group,        -   a —SO₂—NR_(a)R_(b) group,        -   a —SO₃H group,        -   a —OH group, or        -   a —O—SO₂—OR_(c) group,    -   provided that when X¹ is a —NH—CO— group, Y¹ may further be a        phenyl group optionally substituted by one or two substituent(s)        selected from a halogen atom,    -   a (C₁-C₄)alkyl group, a cyano group, a (C₁-C₅)alkoxy group, a        trifluoromethyl group, a trifluoromethoxy group, a        —SO₂—NR_(a)R_(b) group, a —SO₃H group, a —OH group, a        —O—SO₂—OR_(c) group or a —O—P(═O)—(OR_(c))(OR_(d)) group,    -   or any of its pharmaceutically acceptable salt,

for use in the treatment and/or prevention of a RNA virus infectioncaused by a RNA virus belonging to group IV or V of the Baltimoreclassification.

According to a second aspect, the present invention relates to compoundsof formula (I) as defined above for use in the treatment and/orprevention of a RNA virus infection caused by a RNA virus belonging togroup IV or V of the Baltimore classification, in particular aChikungunya viral infection, a Dengue viral infection, an Influenzaviral infection or a RSV viral infection or a virus-related condition,and even more particularly a RSV viral infection, a Chikungunya viralinfection and a Dengue viral infection or a virus-related condition.

According to a third aspect, the present invention relates a compound offormula (Ia),

-   -   wherein    -   Y¹, R, R′, m, m′,

ring, X², n and Y² are as defined above,

or any of its pharmaceutically acceptable salt,

for use in the treatment and/or prevention of a RNA virus infectioncaused by a RNA virus belonging to group IV or V of the Baltimoreclassification, and in particular a Chikungunya viral infection, aDengue viral infection, an Influenza viral infection or a RSV viralinfection or a virus-related condition.

Still according to this third aspect, the present invention relates tothe compound of formula (Ia) for use as defined above, wherein

ring is a phenylene group or a pyridylene group,

-   -   Y¹ represents a 2-pyridyl group, a 3-pyridyl group or a        pyrazinyl group,    -   n is 1, 2 or 3, m is 0,    -   R′ is a halogen atom, a (C₁-C₂)alkoxy group or a (C₁-C₂)alkyl        group,    -   X² represents a —CO—NH— group, a —SO₂NH— group or a divalent        triazole group,    -   Y² represents        -   a morpholinyl group, a piperidinyl group or a piperazinyl            group, optionally substituted by a (C₁-C₄)alkyl group,        -   a —CR¹R²R³ group, wherein R¹, R² and R³ independently            represent a hydrogen atom or a (C₁-C₂)alkyl group, being            understood that no more than one of R¹, R² and R³ is a            hydrogen atom, or R¹ and R² form together with the carbon            atom bearing them a (C₃-C₆)cycloalkyl group,        -   or alternatively X²—Y² represents a group            —C(═O)—NR_(c)R_(d), wherein R_(c) and R_(d) form, together            with the nitrogen atom a saturated heterocyclic ring,            optionally substituted by one or two (C₁-C₄)alkyl group, by            a cyclopentyl group thus forming a spirocyclopentyl            derivative, or by a trifluoromethyl group,    -   or any of its pharmaceutically acceptable salt.

Still according to said third aspect, the present invention furtherrelates to compounds of formula (Ia) as defined above, wherein

ring is a phenylene group or a pyridylene group,

-   -   Y¹ represents a 2-pyridyl group,    -   n is 2, m is 0, R′ is a halogen atom, a (C₁-C₂)alkoxy group or a        (C₁-C₂)alkyl group,    -   Y² represents a —CR¹R²R³ group, wherein R¹, R² and R³        independently represent a hydrogen atom or a (C₁-C₂)alkyl group,        being understood that no more than one of R¹, R² and R³ is a        hydrogen atom, or R¹ and R² form together with the carbon atom        bearing them a (C₃-C₆)cycloalkyl group,    -   or any of its pharmaceutically acceptable salt,

for use in the treatment and/or prevention of a RNA virus infectioncaused by a RNA virus belonging to group IV or V of the Baltimoreclassification, and in particular a Chikungunya viral infection, aDengue viral infection, an Influenza viral infection or a RSV viralinfection or a virus-related condition.

According to a fourth aspect, the present invention relates to acompound of formula (Ib),

-   -   wherein    -   Y¹, R, R′, m, m′,

ring, X², n and Y² are as defined above,

or any of its pharmaceutically acceptable salt,

for use in the treatment and/or prevention of a RNA virus infectioncaused by a RNA virus belonging to group IV or V of the Baltimoreclassification, and in particular a Chikungunya viral infection, aDengue viral infection, an Influenza viral infection or a RSV viralinfection or a virus-related condition.

Still according to this fourth aspect, the present invention relates tothe compound of formula (Ib) for use as defined above, wherein

ring is a phenylene group,

-   -   Y¹ is a phenyl group, a 2-pyridyl group or a pyrimidinyl group        with one of the nitrogen atom of the pyrimidinyl group being in        the ortho position with respect to the —NH—CO— group,    -   n is 1, 2 or 3, m is 0, m′ is 0 or 1,    -   R′ is a (C₃-C₆)cycloalkyl group,    -   X² represents a —CO—NH— group, a —O— group or a divalent        triazole,    -   Y² represents        -   a hydroxyl group,        -   a morpholinyl group, a piperidinyl group or a piperazinyl            group, optionally substituted by a (C₁-C₄)alkyl group,        -   a —CR¹R²R³ group, wherein R¹, R² and R³ independently            represent a hydrogen atom or a (C₁-C₂)alkyl group, being            understood that no more than one of R¹, R² and R³ is a            hydrogen atom, or R¹ and R² form together with the carbon            atom bearing them a (C₃-C₆)cycloalkyl group, said            (C₃-C₆)cycloalkyl group being optionally interrupted on said            R¹ and/or R² by an oxygen atom,    -   or any of its pharmaceutically acceptable salt.

Still according to said fourth aspect, the present invention furtherrelates to compounds of formula (Ib) as defined above,

-   -   wherein

ring is a phenylene group,

-   -   Y¹ is a 2-pyridyl group or a pyrimidinyl group with one of the        nitrogen atom of the pyrimidinyl group being in the ortho        position with respect to the —NH—CO— group,    -   n is 1 or 2, m and m′ are 0,    -   X² represents a —CO—NH— group,    -   Y² represents a —CR¹R²R³ group, wherein R¹, R² and R³        independently represent a hydrogen atom or a (C₁-C₂)alkyl group,        being understood that no more than one of R¹, R² and R³ is a        hydrogen atom, or R¹ and R² form together with the carbon atom        bearing them a (C₃-C₆)cycloalkyl group, said (C₃-C₆)cycloalkyl        group being optionally interrupted on said R¹ and/or R² by an        oxygen atom,    -   or any of its pharmaceutically acceptable salt,

for use in the treatment and/or prevention of a RNA virus infectioncaused by a RNA virus belonging to group IV or V of the Baltimoreclassification, and in particular a Chikungunya viral infection, aDengue viral infection, an Influenza viral infection or a RSV viralinfection or a virus-related condition.

According to a fifth aspect, the present invention relates to a compoundof formula (Id),

-   -   wherein    -   Y¹, R, R′, m, m′,

ring, X², n and Y² are as defined above,

-   -   or any of its pharmaceutically acceptable salt,

for use in the treatment and/or prevention of a RNA virus infectioncaused by a RNA virus belonging to group IV or V of the Baltimoreclassification, and in particular a Chikungunya viral infection, aDengue viral infection, an Influenza viral infection or a RSV viralinfection or a virus-related condition.

Still according to this fifth aspect, the present invention relates tothe compound of formula (Id) for use as defined above, wherein

ring is a phenylene group,

-   -   Y¹ represents a 2-pyridyl group or a 3-pyridyl group,    -   X² represents a —CO—NH— group, a —SO₂—NH— group or a divalent        triazole,    -   m′ and m are 0, n is 1, 2 or 3,    -   Y² represents a hydroxyl or a —CR¹R²R′ group, wherein R¹, R² and        R³ independently represent a hydrogen atom or a (C₁-C₂)alkyl        group, being understood that no more than one of R¹, R² and R³        is a hydrogen atom, or R¹ and    -   R² form together with the carbon atom bearing them a        (C₃-C₆)cycloalkyl group,    -   or any of its pharmaceutically acceptable salt.

Still according to said fifth aspect, the present invention furtherrelates to compounds of formula (Id), wherein

ring is a phenylene group,

-   -   the group

is in meta position on the

ring with respect to the —NH— group,

-   -   Y¹ represents a 2-pyridyl group,    -   m′ and m are 0, n is 2,    -   Y² represents a —CR¹R²R³ group, wherein R¹, R² and R³        independently represent a hydrogen atom or a (C₁-C₂)alkyl group,        being understood that no more than one of R¹, R² and R³ is a        hydrogen atom, or R¹ and R² form together with the carbon atom        bearing them a (C₃-C₆)cycloalkyl group,    -   or any of its pharmaceutically acceptable salt,    -   for use in the treatment and/or prevention of a RNA virus        infection caused by a RNA virus belonging to group IV or V of        the Baltimore classification, and in particular a Chikungunya        viral infection, a Dengue viral infection, an Influenza viral        infection or a RSV viral infection or a virus-related condition.

The above-mentioned compounds (I), (Ia), (Ib) and (Id) are particularlysuitable for treating or preventing a virus infection or relatedcondition, in particular a RNA virus infection caused by a RNA virusbelonging to group IV or V of the Baltimore classification or relatedcondition, and most preferably a Chikungunya viral infection, a Dengueviral infection, an Influenza viral infection or a RSV viral infectionor a virus-related condition.

The above-mentioned compounds are even more particularly suitable fortreating or preventing a Chikungunya viral infection, a Dengue viralinfection or a RSV viral infection or a virus-related condition, mostparticularly a RSV viral infection.

Further aspects of the present invention will be described herein aftersuch as the use of new compounds of formula (I), (Ia), (Ib) and (Id) asa medicament, a pharmaceutical composition and a synthetic process.

According to a particular embodiment, a subject-matter of the presentdocument describes a compound of formula (I) as defined above, whereinthe alkenylene group is a (E)-alkenylene group,

-   -   m and m′ are independently 0 or 1,    -   Y² represents a —CR¹R²R³ group, wherein R¹, R² and R³        independently represent a hydrogen atom, a fluorine atom or a        (C₁-C₂)alkyl group, being understood that no more than one of        R¹, R² and R³ is a hydrogen atom, or R¹ and R² form together        with the carbon atom bearing them a (C₃-C₆)cycloalkyl group,        said (C₃-C₆)cycloalkyl group being optionally substituted by one        or two halogen atoms and said (C₃-C₆)cycloalkyl group being        optionally interrupted on said R¹ and/or R² by an oxygen atom,    -   R and R′ independently represent a halogen atom, a (C₁-C₂)alkyl        group, a (C₃-C₆)cycloalkyl group, or a (C₁-C₂)alkoxy group,    -   or any of its pharmaceutically acceptable salt,

for use in the treatment and/or prevention of a RNA virus infectioncaused by a RNA virus belonging to group IV or V of the Baltimoreclassification, and in particular a Chikungunya viral infection a Dengueviral infection, an Influenza viral infection or a RSV viral infectionor a virus-related condition.

According to a further embodiment, the present document describes acompound of formula (I)

-   -   wherein:

ring and

ring independently mean a phenylene or a pyridylene group,

-   -   wherein the group

is in meta or para position on the

ring, with respect to the —NH— group,

-   -   X¹ represents an alkenylene group, a —NH—CO— group, a —CO—NH—        group, a —CR_(a)R_(b)O— group,    -   Y¹ represents an aryl group selected from a 2-pyridyl group or a        pyrimidinyl group, wherein one of the nitrogen atom of the        pyrimidinyl group is in ortho position with respect to X¹,    -   or alternatively X¹—Y¹ represents a group (A) of formula

-   -   X² represents a —CO—NH— group, a —NH—CO—NH— group, a —OCH₂—        group, a —NH—CO— group or a —SO₂—NH— group,    -   n is 0, 1, 2 or 3,    -   m and m′ are independently 0, 1 or 2,    -   Y² represents a hydrogen atom, a hydroxyl group or a —CR¹R²R³        group, wherein R¹, R² and R³ independently represent a hydrogen        atom, a fluorine atom or a (C₁-C₄)alkyl group, being understood        that no more than one of R¹, R² and R³ is a hydrogen atom, or R¹        and R² form together with the carbon atom bearing them a        (C₃-C₈)cycloalkyl group, said (C₃-C₈)cycloalkyl group being        optionally substituted by one or two (C₁-C₄)alkyl group, halogen        atom or (C₁-C₄)alkoxy group and said (C₃-C₈)cycloalkyl group        being optionally interrupted on said R¹ and/or R² by an oxygen        atom,    -   R and R′ independently represent a halogen atom, a (C₁-C₄)alkyl        group, a (C₃-C₆)cycloalkyl group, a (C₁-C₅)alkoxy group, a        —SO₂—NR_(a)R_(b) group, a —SO₃H group, a —OH group, a        —O—SO₂—OR_(c) group or a —O—P(═O)—(OR_(c))(OR_(d)) group,    -   R_(a), R_(b), R_(c) and R_(d) independently represent a hydrogen        atom or a (C₁-C₄)alkyl group,    -   provided that when X¹ is a —CR_(a)R_(b)O— group, Y¹ may further        be a 3-pyridyl, a 4-pyridyl or a phenyl group optionally        substituted by one or two substituent(s) selected from a halogen        atom, a (C₁-C₄)alkyl group, a cyano group, a (C₁-C₅)alkoxy        group, a trifluoromethyl group, a trifluoromethoxy group, a        —SO₂—NR_(a)R_(b) group, a —SO₃H group, a —OH group, a        —O—SO₂—OR_(c) group or a —O—P(═O)—(OR_(c))(OR_(d)) group,    -   and provided that when Y¹—X¹ represents a 2-pyridylethenylene        group, X² represents a —CO—NH— group and Y² represents a        —CR¹R²R³ group, wherein R¹, R² and R³ independently represent a        hydrogen atom or a (C₁-C₄)alkyl group, and    -   m′ is different from 0,    -   or any of its pharmaceutically acceptable salt,    -   for use in the treatment and/or prevention of a RNA virus        infection caused by a RNA virus belonging to group IV or V of        the Baltimore classification.

Still according to a particular embodiment, the present invention isdirected to new compounds, encompassed within formula (I).

Said new compounds, which may also be under the form of acceptablesalts, are selected from

-   -   (1) a compound of formula (Ia) as defined above for formula (I)    -   wherein    -   Y¹ is a 2-pyridyl group, 3-pyridyl or a pyrazinyl group,    -   the group

is in meta position on the

ring with respect to the —NH— group,

-   -   X², Y², n, R, R′, m and m′ are as defined above,    -   the

ring is a phenylene group, and

-   -   with the proviso that compounds 1 and 2 as defined herein after        are excluded,    -   (2) a compound of formula (Ib) as defined above for formula (I)    -   wherein    -   Y¹ is a phenyl group, a 2-pyridyl group or a pyrimidinyl group        with one of the nitrogen of the pyrimidinyl group being in the        ortho position with respect to X¹, X², Y², n, R, R′,

ring, m and m′ are as defined above, and

-   -   (4) a compound of formula (Id) as defined above for formula (I)    -   wherein    -   Y¹ is a 2-pyridyl group or a 3-pyridyl group, and    -   R, R′, m, m′,

ring, X², n and Y² are as defined above.

According to another aspect, a subject-matter of the present inventionrelates to a new compound of formula (Ia), (Ib), and (Id) as definedjust above or any of its pharmaceutically acceptable salts, and any ofcompounds (3) to (18), (32) to (35), (91) to (122) as defined hereinafter or any of its pharmaceutically acceptable salts, for use as amedicament.

Any combination of the above-defined embodiments for R, R′, m, m′,

ring,

ring, X¹, X², n, Y¹, Y² with each other does form part of the instantinvention.

According to a particular embodiment, the present invention relates to acompound of formula (I) for use as defined above, wherein

ring and

ring both represent a phenylene group.

According to a particular embodiment, a subject-matter of the presentdocument describes a compound of formula (Ia) as defined above,

-   -   wherein    -   the alkenylene group is a (E)-alkenylene group,    -   m and m′ are independently 0 or 1,    -   Y² represents a —CR¹R²R³ group, wherein R¹, R² and R³        independently represent a hydrogen atom, a fluorine atom or a        (C₁-C₂)alkyl group, being understood that no more than one of        R¹, R² and R³ is a hydrogen atom, or R¹ and R² form together        with the carbon atom bearing them a (C₃-C₆)cycloalkyl group,        said (C₃-C₆)cycloalkyl group being optionally substituted by one        or two halogen atoms and said (C₃-C₆)cycloalkyl group being        optionally interrupted on said R¹ and/or R² by an oxygen atom,    -   R and R′ independently represent a halogen atom, a (C₁-C₂)alkyl        group, a (C₃-C₆)cycloalkyl group, or a (C₁-C₂)alkoxy group,    -   or any of its pharmaceutically acceptable salt,

for use in the treatment and/or prevention of a RNA virus infectioncaused by a RNA virus belonging to group IV or V of the Baltimoreclassification, and in particular a Chikungunya viral infection a Dengueviral infection, an Influenza viral infection or a RSV viral infectionor a virus-related condition.

According to a particular embodiment, a subject-matter of the presentdocument describes a compound of formula (Ib) as defined above,

-   -   wherein    -   m and m′ are independently 0 or 1,    -   Y² represents a —CR¹R²R³ group, wherein R¹, R² and R³        independently represent a hydrogen atom, a fluorine atom or a        (C₁-C₂)alkyl group, being understood that no more than one of        R¹, R² and R³ is a hydrogen atom, or R¹ and R² form together        with the carbon atom bearing them a (C₃-C₆)cycloalkyl group,        said (C₃-C₆)cycloalkyl group being optionally substituted by one        or two halogen atoms and said (C₃-C₆)cycloalkyl group being        optionally interrupted on said R¹ and/or R² by an oxygen atom,    -   R and R′ independently represent a halogen atom, a (C₁-C₂)alkyl        group, a (C₃-C₆)cycloalkyl group, or a (C₁-C₂)alkoxy group,    -   or any of its pharmaceutically acceptable salt,

for use in the treatment and/or prevention of a RNA virus infectioncaused by a RNA virus belonging to group IV or V of the Baltimoreclassification, and in particular a Chikungunya viral infection a Dengueviral infection, an Influenza viral infection or a RSV viral infectionor a virus-related condition.

According to a particular embodiment, a subject-matter of the presentdocument describes a compound of formula (Id) as defined above,

-   -   wherein    -   m and m′ are independently 0 or 1,    -   Y² represents a —CR¹R²R³ group, wherein R¹, R² and R³        independently represent a hydrogen atom, a fluorine atom or a        (C₁-C₂)alkyl group, being understood that no more than one of        R¹, R² and R³ is a hydrogen atom, or R¹ and R² form together        with the carbon atom bearing them a (C₃-C₆)cycloalkyl group,        said (C₃-C₆)cycloalkyl group being optionally substituted by one        or two halogen atoms and said (C₃-C₆)cycloalkyl group being        optionally interrupted on said R¹ and/or R² by an oxygen atom,    -   R and R′ independently represent a halogen atom, a (C₁-C₂)alkyl        group, a (C₃-C₆)cycloalkyl group, or a (C₁-C₂)alkoxy group,    -   or any of its pharmaceutically acceptable salt,

for use in the treatment and/or prevention of a RNA virus infectioncaused by a RNA virus belonging to group IV or V of the Baltimoreclassification, and in particular a Chikungunya viral infection a Dengueviral infection, an Influenza viral infection or a RSV viral infectionor a virus-related condition.

In another embodiment, the present invention relates to the compounds offormula (I) for use as defined above,

-   -   wherein        -   Y¹ represents        -   a 2-pyridinyl group or a 3-pyridinyl group,        -   a pyrimidinyl group or a pyrazinyl group, with one of the            nitrogen atoms being in ortho position with respect to X¹,    -   provided that when X¹ is a —NH—CO— group, Y¹ may further be a        phenyl group,    -   or any of its pharmaceutically acceptable salt.

In another embodiment, in the compounds of formula (I), for use asdefined above, wherein

-   -   X² represents        -   a —O— group,        -   a —CO—NH— group,        -   a divalent triazole,        -   or        -   a —SO₂—NH— group,    -   or any of its pharmaceutically acceptable salt.

In another embodiment, the present invention relates to the compound offormula (I), for use as defined above, wherein

-   -   Y² represents        -   a hydroxyl group,        -   a morpholinyl group,        -   a piperidinyl group, optionally substituted by a            (C₁-C₄)alkyl group,        -   a piperazinyl group, optionally substituted by a            (C₁-C₄)alkyl group,        -   or        -   a —CR¹R²R′ group, wherein R¹, R² and R³ independently            represent a hydrogen atom, a fluorine atom or a (C₁-C₄)alkyl            group, being understood that no more than one of R¹, R² and            R³ is a hydrogen atom, or R¹ and R² form together with the            carbon atom bearing them a (C₃-C₈)cycloalkyl group,    -   or any of its pharmaceutically acceptable salt.

In another embodiment, the present invention relates to the compound offormula (I), for use as defined above, wherein

-   -   R and R′ independently represent        -   a (C₁-C₄)alkyl group,        -   a (C₃-C₆)cycloalkyl group,        -   a halogen atom, or        -   a (C₁-C₅)alkoxy group,    -   or any of its pharmaceutically acceptable salt.

Any combination of the above-defined embodiments for R, R′, m, m′,

ring,

ring, X¹, X², n, Y¹, Y² with each other does form part of the instantinvention.

In another embodiment, the present invention relates to the compound offormula (I), for use as defined above, wherein

ring and

ring both represent a phenylene group,

-   -   R″ is a hydrogen atom,    -   Y¹ represents a 2-pyridinyl group provided that when X¹ is a        —NH—CO— group, Y¹ may further be a phenyl group,    -   X² represents a —O— group, a —CO—NH— group,    -   Y² represents a —CR¹R²R³ group, wherein R¹ and R² form together        with the carbon atom bearing them a (C₃-C₈)cycloalkyl group and        R³ represents a hydrogen atom or a (C₁-C₄)alkyl group, and    -   R and R′ represents a hydrogen atom or a (C₃-C₆)cycloalkyl        group, such as a cyclopropyl group,    -   or any of its pharmaceutically acceptable salt.

According to a preferred embodiment of the present invention, thecompound of formula (I) is chosen from:

-   (1)    (E)-N-isopentyl-3-((4-(2-(pyridin-2-yl)vinyl)phenyl)amino)benzamide-   (2)    (E)-N-isopentyl-4-((4-(2-(pyridin-2-yl)vinyl)phenyl)amino)benzamide-   (3)    (E)-N-isopentyl-3-((3-methoxy-4-(2-(pyridin-2-yl)vinyl)phenyl)amino)benzamide-   (4)    (E)-N-(2-cyclohexylethyl)-3-((4-(2-(pyridin-2-yl)vinyl)phenyl)amino)benzamide-   (5)    (E)-N-neopentyl-3-((4-(2-(pyridin-2-yl)vinyl)phenyl)amino)benzamide-   (6)    (E)-N-(2-cyclopentylethyl)-3-((4-(2-(pyridin-2-yl)vinyl)phenyl)amino)benzamide-   (7)    (E)-N-isopentyl-3-((4-(2-(pyridin-2-yl)vinyl)phenyl)amino)benzenesulfonamide-   (8)    (E)-N-(2-cyclopropylethyl)-3-((4-(2-(pyridin-2-yl)vinyl)phenyl)amino)benzamide-   (9)    (E)-N-(2-cyclobutylethyl)-3-((4-(2-(pyridin-2-yl)vinyl)phenyl)amino)benzamide-   (10)    (E)-N-(2-cyclopentylethyl)-6-((4-(2-(pyridin-2-yl)vinyl)phenyl)amino)picolinamide-   (11)    (E)-N-(2-cyclohexylethyl)-3-((3-fluoro-4-(2-(pyridin-2-yl)vinyl)phenyl)amino)benzamide-   (12)    (E)-N-(2-cyclopentylethyl)-3-((2-methyl-4-(2-(pyridin-2-yl)vinyl)phenyl)amino)benzamide-   (13)    (E)-N-isopentyl-3-((2-methyl-4-(2-(pyridin-2-yl)vinyl)phenyl)amino)benzamide-   (14) N-isopentyl-3-((4-(pyridin-2-ylcarbamoyl)phenyl)amino)benzamide-   (15)    N-(2-cyclopentylethyl)-3-((4-(pyridin-2-ylcarbamoyl)phenyl)amino)benzamide-   (16)    N-(2-cyclohexylethyl)-3-((4-(pyridin-2-ylcarbamoyl)phenyl)amino)benzamide-   (17)    N-(2-cyclopentylethyl)-3-((4-(pyrimidin-4-ylcarbamoyl)phenyl)amino)benzamide-   (18)    N-isopentyl-3-((4-(pyrimidin-2-ylcarbamoyl)phenyl)amino)benzamide-   (32) N-(4-((3-(isopentylcarbamoyl)phenyl)amino)phenyl)picolinamide-   (33) N-(4-((3-(neopentylcarbamoyl)phenyl)amino)phenyl)picolinamide-   (34) N-(4-((3-(N-isopentylsulfamoyl)phenyl)amino)phenyl)picolinamide-   (35)    N-(4-((3-((2-cyclopentylethyl)carbamoyl)phenyl)amino)phenyl)picolinamide-   (91)    3-({3-methoxy-4-[(E)-2-(pyridin-3-yl)ethenyl]phenyl}amino)-N-[3-(morpholin-4-yl)propyl]benzamide-   (92)    3-({2-methyl-4-[(E)-2-(pyridin-3-yl)ethenyl]phenyl}amino)-N-[3-(morpholin-4-yl)propyl]benzamide-   (93)    N-(2-cyclopentylethyl)-3-({4-[(E)-2-(pyridin-3-yl)ethenyl]phenyl}amino)benzene-1-sulfonamide-   (94)    4-[(E)-2-(pyridin-2-yl)ethenyl]-N-{3-[4-(trifluoromethyl)piperidine-1-carbonyl]phenyl}aniline-   (95)    N-(3-methylbutyl)-3-({4-[(E)-2-(pyrazin-2-yl)ethenyl]phenyl}amino)benzamide-   (96)    N-(2-cyclopentylethyl)-3-({4-[(E)-2-(pyrazin-2-yl)ethenyl]phenyl}amino)benzamide-   (97)    N-[3-(4,4-dimethylpiperidine-1-carbonyl)phenyl]-4-[(E)-2-(pyridin-2-yl)ethenyl]aniline-   (98)    N-(3-{8-azaspiro[4.5]decane-8-carbonyl}phenyl)-4-[(E)-2-(pyridin-2-yl)ethenyl]aniline-   (99)    3-[4-(2-methylpropyl)-1H-1,2,3-triazol-1-yl]-N-{4-[(E)-2-(pyridin-2-yl)ethenyl]phenyl}aniline-   (100)    3-[4-(2-methylpropyl)-1H-1,2,3-triazol-1-yl]-N-{4-[(E)-2-(pyridin-3-yl)ethenyl]phenyl}aniline-   (101)    N-(3-methylbutyl)-3-({4-[(E)-2-(pyridin-3-yl)ethenyl]phenyl}amino)benzamide-   (102)    N-(3-methylbutyl)-3-({4-[(E)-2-(pyridin-3-yl)ethenyl]phenyl}amino)benzene-1-sulfonamide-   (103)    N-(2-cyclopentylethyl)-3-({4-[(E)-2-(pyridin-3-yl)ethenyl]phenyl}amino)benzamide-   (104)    N-(2,2-dimethylpropyl)-3-({4-[(E)-2-(pyridin-3-yl)ethenyl]phenyl}amino)benzamide-   (105)    N-(2-cyclohexylethyl)-3-({4-[(E)-2-(pyridin-3-yl)ethenyl]phenyl}amino)benzamide-   (106)    N-[3-(morpholin-4-yl)propyl]-3-({4-[(E)-2-(pyridin-2-yl)ethenyl]phenyl}amino)benzene-1-sulfonamide-   (107)    N-[3-(morpholin-4-yl)propyl]-2-({4-[(E)-2-(pyridin-2-yl)ethenyl]phenyl}amino)pyridine-4-carboxamide-   (108)    N-[3-(morpholin-4-yl)propyl]-6-({4-[(E)-2-(pyridin-2-yl)ethenyl]phenyl}amino)pyridine-2-carboxamide-   (109)    N-[3-(4-methylpiperazin-1-yl)propyl]-2-({4-[(E)-2-(pyridin-2-yl)ethenyl]phenyl}amino)pyridine-4-carboxamide-   (110)    N-[3-(4-methylpiperazin-1-yl)propyl]-6-({4-[(E)-2-(pyridin-2-yl)ethenyl]phenyl}amino)pyridine-2-carboxamide-   (111)    N-[3-(morpholin-4-yl)propyl]-3-({4-[(E)-2-(pyridin-2-yl)ethenyl]phenyl}amino)benzamide-   (112)    N-[3-(piperidin-1-yl)propyl]-3-({4-[(E)-2-(pyridin-2-yl)ethenyl]phenyl}amino)benzamide-   (113)    N-[3-(4-methylpiperazin-1-yl)propyl]-3-({4-[(E)-2-(pyridin-2-yl)ethenyl]phenyl}amino)benzamide-   (114)    3-{4-[(diethylamino)methyl]-1H-1,2,3-triazol-1-yl}-N-{4-[(E)-2-(pyridin-2-yl)ethenyl]phenyl}aniline-   (115)    4-{[3-(3-cyclohexylpropoxy)phenyl]amino}-3-cyclopropyl-N-phenylbenzamide-   (116)    3-cyclopropyl-4-({2-[(3-methylbutyl)carbamoyl]phenyl}amino)-N-(pyrimidin-2-yl)benzamide-   (117)    3-cyclopropyl-N-(pyrimidin-2-yl)-4-({2-[(3,3,3-trifluoropropyl)carbamoyl]phenyl}amino)benzamide-   (118)    4-[(3-{[3-(morpholin-4-yl)propyl]carbamoyl}phenyl)amino]-N-(pyridin-2-yl)benzamide-   (119)    4-[(3-{[3-(piperidin-1-yl)propyl]carbamoyl}phenyl)amino]-N-(pyridin-2-yl)benzamide-   (120)    4-[(3-{[3-(4-methylpiperazin-1-yl)propyl]carbamoyl}phenyl)amino]-N-(pyridin-2-yl)benzamide-   (121)    4-({3-[4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]phenyl}amino)-N-(pyridin-2-yl)benzamide-   (122)    N-[4-({3-[4-(2-methylpropyl)-1H-1,2,3-triazol-1-yl]phenyl}amino)phenyl]pyridine-2-carboxamide

and their pharmaceutically acceptable salts.

The present invention extends to compounds (3) to (18), (32) to (35),(91) to (122) and their pharmaceutically acceptable salts, such ashydrobromide, tartrate, citrate, trifluoroacetate, ascorbate,hydrochloride, tosylate, triflate, maleate, mesylate, formate, acetateand fumarate.

According to another aspect, a subject-matter of the present inventionrelates to a compound of formula (I), (Ia), (Ib) and (Id) as definedabove or any of its pharmaceutically acceptable salts, and any ofcompounds (1) to (18), (32) to (35) and (91) to (122) or any of itspharmaceutically acceptable salts, for use as an agent for preventing,inhibiting or treating a RNA virus infection caused by a RNA virusbelonging to group IV or V of the Baltimore classification.

Compounds of formula (I) as defined above for which

ring and

ring both represent a phenylene group,

-   -   Y¹ represents a 2-pyridinyl group provided that when X¹ is a        —NH—CO— group, Y¹ may further be a phenyl group,    -   X² represents a —O— group, a —CO—NH— group,    -   Y² represents        -   a —CR¹R²R³ group, wherein R¹, R² and R³ independently            represent a hydrogen atom, or a (C₁-C₄)alkyl group, being            understood that no more than one of R¹,        -   R² and R³ is a hydrogen atom, or R¹ and R² form together            with the carbon atom bearing them a (C₃-C₈)cycloalkyl group            and R³ represents a hydrogen atom or a (C₁-C₄)alkyl group,            or        -   a morpholinyl group, and    -   R and R′ independently represent a hydrogen atom, (C₁-C₄)alkyl        group, such as a methyl group, or a (C₃-C₆)cycloalkyl group,        such as a cyclopropyl group,

or any of its pharmaceutically acceptable salt, may be particularlysuitable for use as an agent for preventing, inhibiting or treating aRNA virus infection caused by a RNA virus belonging to group IV or V ofthe Baltimore classification.

Compounds (12), (13), (15) and (35) or any of their pharmaceuticallyacceptable salts may be particularly useful for preventing, inhibitingor treating dengue infection.

Compounds (12), (13), (16) and (115) or any of their pharmaceuticallyacceptable salts may be particularly useful for preventing, inhibitingor treating RSV infection.

Compounds (1), (2), (4), (6), (9), (12), (13), (14), (15), (16), (32),(35) or any of their pharmaceutically acceptable salts may beparticularly useful for preventing, inhibiting or treating Chikungunyainfection.

The compounds of the invention may exist in the form of free bases or ofaddition salts with pharmaceutically acceptable acids.

«Pharmaceutically acceptable salt thereof» refers to salts which areformed from acid addition salts formed with inorganic acids (e.g.hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,nitric acid, and the like), as well as salts formed with organic acidssuch as acetic acid, oxalic acid, tartaric acid, succinic acid, malicacid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannicacid, palmoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalene disulfonic acid, and poly-galacturonic acid.

Suitable physiologically acceptable acid addition salts of compounds offormula (I) include hydrobromide, tartrate, citrate, trifluoroacetate,ascorbate, hydrochloride, tosylate, triflate, maleate, mesylate,formate, acetate and fumarate.

The compounds of formula (I), (Ia), (Ib) and (Id) and any of compounds(1) to (18), (32) to (35) and (91) to (122) or any of theirpharmaceutically acceptable salts may form solvates or hydrates and theinvention includes all such solvates and hydrates.

The terms “hydrates” and “solvates” simply mean that the compounds (I),(Ia), (Ib) and (Id) according to the invention can be in the form of ahydrate or solvate, i.e. combined or associated with one or more wateror solvent molecules. This is only a chemical characteristic of suchcompounds, which can be applied for all organic compounds of this type.

In the context of the present invention, the term:

-   -   “halogen” is understood to mean chlorine, fluorine, bromine, or        iodine, and in particular denotes chlorine, fluorine or bromine,    -   “(C₁-C_(x))alkyl”, as used herein, respectively refers to a        C₁-C_(x) normal, secondary or tertiary saturated hydrocarbon,        for example (C₁-C₆)alkyl. Examples are, but are not limited to,        methyl, ethyl, 1-propyl, 2-propyl, butyl, pentyl,    -   an “alkenylene” means a divalent (C₁-C_(x))alkyl group        comprising a double bond, and more particularly an ethenylene        group, also known as vinylene or 1,2-ethenediyl,    -   “(C₃-C₆)cycloalkyl”, as used herein, refers to a cyclic        saturated hydrocarbon. Examples are, but are not limited to,        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    -   “(C₃-C₆)cycloalkenyl”, as used herein, refers to a cyclic non        aromatic hydrocarbon comprising at least one unsaturated bond.        Examples are, but not limited to, cyclopentenyl and        cyclohexenyl,    -   “(C₁-C_(x))alkoxy”, as used herein, refers to a O—(C₁-Cx)alkyl        moiety, wherein alkyl is as defined above, for example        (C₁-C₆)alkoxy. Examples are, but are not limited to, methoxy,        ethoxy, 1-propoxy, 2-propoxy, butoxy, pentoxy,    -   “aryl”, as used herein, refers to a monocyclic aromatic group        containing 6 carbon atoms and containing between 0 and 2        heteroatoms, such as nitrogen, oxygen or sulphur, and in        particular nitrogen. By way of examples of aryl groups, mention        may be made of, but not limited to: phenyl, pyridine,        pyrimidine, pyridazine, pyrazine and the like. In the framework        of the present invention, the aryl is advantageously phenyl,        pyridazine, pyrazine, pyridine, such as 2-pyridine or 3-pyridine        and pyrimidine. The aryl is even more advantageously phenyl and        pyridine, such as 2-pyridine or 3-pyridine.    -   a “divalent 5-membered heteroaromatic ring comprising 1, 2, 3 or        4 heteroatoms” as used herein, means a divalent ring consisting        of an aromatic ring comprising 5 chains and 1, 2, 3 or 4        heteroatoms selected from nitrogen and oxygen atoms. In one        embodiment, it comprises at least 1 heteroatom, and preferably        at least one nitrogen atom. In another embodiment, it comprises        at least 2 heteroatoms, with for example at least one nitrogen        atom. According to a further embodiment, it comprises 2, 3 or 4        nitrogen atoms, preferably 3 nitrogen atoms. According to an        even further embodiment, it comprises one nitrogen atom and one        oxygen atom or two nitrogen atoms and one oxygen atom. Examples        are, but not limited to, divalent triazole, such as 1,2,3- or        1,2,4-triazoles, oxadiazoles, such as 1,2,4-oxadiazole or        1,2,3-oxadiazole and divalent diazoles such as divalent diazole        and divalent imidazole. According to a preferred embodiment,        such divalent 5-membered heteroaromatic ring comprising 2 or 3        heteroatoms is a divalent triazole.

The compounds of formula (I), (Ia), (Ib) and (Id) can comprise one ormore asymmetric carbon atoms. They can thus exist in the form ofenantiomers or of diastereoisomers. These enantiomers, diastereoisomersand their mixtures, including the racemic mixtures, are encompassedwithin the scope of the present invention.

The compounds of the present invention can be prepared by conventionalmethods of organic synthesis practiced by those skilled in the art. Thegeneral reaction sequences outlined below represent a general methoduseful for preparing the compounds of the present invention and are notmeant to be limiting in scope or utility.

The compounds of general formula (I) can be prepared according to scheme1 below.

The synthesis is based on a coupling reaction starting from a halogenoaromatic compound of formula (III), wherein R, R′, m, m′,

ring,

ring, X¹, X², n, Y¹, Y² are as defined above and X is a chlorine atom,an iodine atom or a bromine atom.

According to one embodiment, procedure (A1) may advantageously be usedwhen the group

is in meta or para position on the

ring, with respect to the —NH— group.

According to procedure (A1), the compound of formula (III) may be placedin a protic solvent such as tert-butanol. The compound of formula (II)may then be added, for example in a molar ratio ranging from 1 to 1.5with respect to the compound of formula (III) in presence of aninorganic base, such as Cs₂CO₃ or K₂CO₃, for example in a molar ratioranging from 1 to 5 still with respect to the compound of formula (III),in the presence of a diphosphine, such as Xantphos(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene) or X-Phos(2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl) in particular inan amount ranging from 2 mol % to 15 mol % relative to the total amountof compound of formula (III), and in the presence of an organometalliccatalyst, such as Pd(OAc)₂ or Pd₂dba₃, in an amount ranging from 2 mol %to 25 mol % relative to the total amount of compound of formula (III).The reaction mixture can then be heated at a temperature ranging from 80to 130° C., for example at 90° C., and stirred for a time ranging from15 to 25 hours, for example during 20 hours, under inert gas and forexample argon. The reaction mixture can be concentrated under reducedpressure and the residue can be diluted with an organic solvent such asethyl acetate. The organic phase can be washed with water, decanted,dried over magnesium sulphate, filtered and then concentrated underreduced pressure to give a compound of formula (I).

According to one embodiment, procedure (A2) may advantageously be usedwhen the group

is in ortho position on the

ring, with respect to the —NH— group.

According to procedure (A2), the compound of formula (II) may be placedin a polar aprotic solvent such as dimethylsulfoxide. The compound offormula (III) may then be added, for example in a molar ratio rangingfrom 1 to 1.5 with respect to the compound of formula (II) in presenceof an inorganic base, such as Cs₂CO₃ or K₂CO₃, for example in a molarratio ranging from 1 to 5 still with respect to the compound of formula(II), in the presence of a ligand, such as L-proline in particular in anamount ranging from 2 mol % to 25 mol % relative to the total amount ofcompound of formula (II), and in the presence of an organometalliccatalyst, such as CuI, in an amount ranging from 2 mol % to 25 mol %relative to the total amount of compound of formula (II). The reactionmixture can then be heated at a temperature ranging from 80 to 130° C.,for example at 90° C., and stirred for a time ranging from 15 to 25hours, for example during 20 hours, under inert gas and for exampleargon. The reaction mixture can be diluted with an organic solvent suchas ethyl acetate. The organic phase can be washed with water, decanted,dried over magnesium sulphate, filtered and then concentrated underreduced pressure to give a compound of formula (I).

The starting compounds of formula (II), (III) are available or can beprepared according to methods known to the person skilled in the art.

Accordingly, the present invention further relates to the synthesisprocess for manufacturing new compounds of formula (I), (I), (Ia), (Ib)and (Id) as defined above, more particularly new compounds of formula(Ia), (Ib) or (Id), comprising at least a step of coupling a compound offormula (TI)

with a compound of formula (III)

wherein X¹, Y¹, R, R′, m, m′,

ring,

ring, X², Y² are as defined above and X is a chlorine atom, an iodineatom or a bromine atom, in presence of an inorganic base and a ligandand in the presence of an organometallic catalyst, to obtain newcompounds of formula (I), (I), (Ia), (Ib), or (Id), more particularlynew compounds of formula (Ia), (Ib) or (Id).

More particularly, compounds of formula (IIa), when used to preparecompounds of formula (Ia), can be prepared according to scheme 2 below.

Preparation of (IIa) for (Ia)

Intermediate compounds of formulae (IIa) and (IVa) are useful forpreparing compounds of formula (Ia) according to the invention.

According to procedure (B), the bromonitrobenzene derivative may beplaced in a polar solvent such as N,N-dimethylformamide. A vinylaryl,with aryl having the same meaning as above defined, may then be added,for example in a molar ratio ranging from 1 to 1.5 with respect to thebromonitrobenzene derivative, in presence of an inorganic base, such assodium acetate or potassium acetate, in particular in a molar ratioranging from 1 to 3 still with respect to the compound of formula (III),in the presence of a phosphine such as triphenylphosphine, for examplein an amount ranging from 5 mol % to 15 mol % relative to the amount ofthe bromonitrobenzene derivative, and in the presence of anorganometallic catalyst such as Pd(OAc)₂ or Pd₂dba₃ in an amount rangingfrom 2 mol % to 10 mol % relative to the amount of the bromonitrobenzenederivative. The reaction mixture can then be heated at a temperatureranging from 80 to 140° C., for example at 135° C., and stirred for atime ranging from 15 to 30 hours for example 24 hours under inert gasfor example argon. The reaction mixture can be concentrated underreduced pressure and the residue can be diluted with an organic solventsuch as ethyl acetate. The organic phase can be washed with water,decanted, dried over magnesium sulphate, filtered and concentrated underreduced pressure to give a compound of formula (IVa).

According to procedure (C), the compound of formula (IVa) and tin (II)chloride dihydrate, in a ratio ranging from 3 to 8 equivalents, may beplaced in a protic solvent such as ethanol. The reaction mixture canthen be heated at a temperature ranging from 40 to 80° C., for exampleat 60° C. and stirred for a time ranging from 15 to 25 hours, forexample during 20 hours. The mixture can be poured into 1N NaOH aqueoussolution and extracted with an organic solvent such as ethyl acetate.The organic phase can then be washed with water and a saturated aqueoussolution of brine, dried over magnesium sulphate, filtered andconcentrated under reduced pressure to give a compound of formula (IIa).

More particularly, intermediate compounds of formula (IIb) (with atleast one of W¹ or W² being CH), when used to prepare compounds offormula (Ib), can be prepared according to scheme 3 below.

Preparation of (IIb) for (Ib), with at Least (W¹ or W²=CH)

Intermediate compounds of formulae (IIb) and (IVb) are useful forpreparing compounds of formula (Ib) according to the invention.

According to procedure (D1), the aminopyridine (W¹ and W²=CH), added forexample in a molar ratio ranging from 1 to 1.5 with respect to thenitrobenzoyl chloride derivative, may be placed in an aqueous solutionof inorganic base such as sodium hydroxide, for example in a molarconcentration ranging from 2M to 5M. A polar aprotic solvent such asdichloromethane may be added to the solution, the reaction mixture canbe cooled down to 0° C. with an ice bath and a solution of thenitrobenzoyl chloride derivative in a polar aprotic solvent such asdichloromethane can be added dropwise. The reaction mixture can then bestirred at room temperature for a time ranging from 15 to 24 hours, forexample 18 hours, under inert gas for example argon. The resultingprecipitate can be filtered, washed with water and dichloromethane anddried under vacuum overnight to give a compound of formula (IVb).

According to procedure (D2), the aminopyrimidine (W¹ or W²=N and theother W¹ or W²=CH), may be placed in a polar aprotic solvent such asdichloromethane. The nitrobenzoyl chloride derivative may then be added,for example in a molar ratio ranging from 1 to 1.5 with respect to theaminopyrimidine, in presence of an organic base such asN,N-diisopropylethylamine or triethylamine, for example in a molar ratioranging from 1 to 2 still with respect to the aminopyrimidine, in thepresence of a nucleophilic catalyst such as dimethylaminopyridine, forexample in a molar ratio ranging from 0.1 to 1 still with respect to theaminopyrimidine. The reaction mixture can then be stirred at roomtemperature for a time ranging from 5 to 20 hours for example 18 hours,under inert gas and for example argon. The organic phase can be washedwith water and the resulting precipitate can be filtered, washed withwater and dichloromethane and dried under vacuum overnight to give acompound of formula (IVb).

According to procedure (C), the compound of formula (IVb) and tin (II)chloride dihydrate in a ratio ranging from 3 to 8 equivalents may beplaced in a protic solvent such as ethanol. The reaction mixture canthen be heated at a temperature ranging from 40 to 80° C., for exampleat 60° C. and stirred for a time ranging from 15 to 25 hours, forexample during 20 hours. The mixture can be poured into 1N NaOH aqueoussolution and extracted with an organic solvent such as ethyl acetate.The organic phase can then be washed with water and a saturated aqueoussolution of brine, dried over magnesium sulphate, filtered andconcentrated under reduced pressure to give a compound of formula (IIb).

In the case of X¹ being a —NH—CO— group, another route can be followedto prepare compounds of formula (Ib) and is displayed in scheme X below.

The synthesis starts with a coupling reaction of a halogeno aromaticcompound of formula (IIIb) with an aniline derivative (Vb), wherein R,R′, m, m′, X¹, X², n, Y¹, Y² are as defined above and X is a chlorineatom, an iodine atom or a bromine atom, following procedure (A1) or(A2).

According to procedure (K), the compound of formula (VIb) may be placedin a protic solvent such as methanol and an aqueous solution of 2M NaOHmay be added in a ratio ranging from 3 to 10 equivalents. The reactionmixture can then be heated at a temperature ranging from 50 to 90° C.,for example at 80° C. and stirred for a time ranging from 1 to 24 hours,for example during 3 hours. The mixture can be concentrated underreduced pressure and, after addition of an aqueous solution of 2M HCl,extracted with an organic solvent such as dichloromethane. The combinedorganic phases can then be dried over magnesium sulphate, filtered andconcentrated under reduced pressure to give a compound of formula(VIIb).

According to procedure (L), the compound of formula (VIIb) and the aminederivative Y¹—NH₂, in a ratio ranging from 1.0 to 3 equivalents, forexample 1.2 equivalent, may be placed in an anhydrous polar solvent suchas N,N-dimethylformamide. A coupling agent such as HATU may then beadded, for example in a molar ratio ranging from 1 to 2 with respect tocompound (VIIb), in presence of an organic base such as triethylamine orN,N-diisopropylethylamine, for example in a molar ratio ranging from 2to 5 still with respect to compound (VIIb). The reaction mixture canthen be stirred at room temperature for a time ranging from 5 to 20hours, for example 16 hours. The reaction can be quenched upon additionof an aqueous solution of 1M hydrochloric acid and the mixture extractedwith an organic solvent such as ethyl acetate. The combined organicphases can then be dried over magnesium sulphate, filtered andconcentrated under reduced pressure to afford a compound of formula(Ib).

More particularly, compounds of formula (IId), when used to preparecompounds of formula (Id), can be prepared according to scheme 5 below.

Preparation of (IId) for (Id)

Intermediate compounds of formulae (IId), (IVd) and (Vd) are useful forpreparing compounds of formula (Id) according to the invention.

According to procedure (F), the 1,4-benzenediamine derivative may beplaced in a mixture of polar solvents such as N,N-dimethylformamide andtetrahydrofurane, for example in a ratio ranging from ¼ to ½. Boc₂O(Di-tert-butyl dicarbonate) may then be added dropwise, for example in amolar ratio ranging from 0.25 to 0.75 with respect to the1,4-benzenediamine derivative in presence of an inorganic base, such asCs₂CO₃ or K₂CO₃, aqueous solution with a concentration ranging from 2Mto 3M and for example in a molar ratio ranging from 0.5 to 1 still withrespect to the 1,4-benzenediamine derivative. The reaction mixture canthen be stirred at room temperature for a time ranging from 10 to 70hours, for example during 64 hours, under inert gas and for exampleargon. The reaction mixture can be concentrated under reduced pressureand the residue can be diluted with an organic solvent such as ethylacetate. The organic phase can be washed with water, decanted, driedover magnesium sulphate, filtered and concentrated under reducedpressure to give a compound of formula (IVd).

According to procedure (G), the amino derivative (IVd) may be placed ina polar aprotic solvent such as dichloromethane. The carboxylic acidderivative may then be added, for example in a molar ratio ranging from1 to 1.5 with respect to the amino derivative (IVd), in presence of acoupling agent such as EDCI·HCl(1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride), forexample in a molar ratio ranging from 1 to 3, in presence of an organicbase such as N,N-diisopropylethylamine or triethylamine, for example ina molar ratio ranging from 1 to 5 still with respect to the aminoderivative (IVd) and in the presence of HOBt (1-Hydroxybenzotriazolehydrate), for example in a molar ratio ranging from 1 to 3 still withrespect to the amino derivative (IVd). The reaction mixture can then bestirred at room temperature for a time ranging from 5 to 30 hours forexample 24 hours, under inert gas and for example argon. The organicphase can be washed with water, decanted, dried over magnesium sulphate,filtered and concentrated under reduced pressure to give a compound offormula (Vd).

According to procedure (H), the compound of formula (Vd) may be placedin a polar aprotic solvent such as dichloromethane. Trifluoroacetic acidmay then be added, for example in a molar ratio ranging from 10 to 30with respect to the amino derivative (IVd). The reaction mixture can bestirred at room temperature for a time ranging from 1 to 7 hours andthen cooled down to 0° C. with an ice bath. Water and an inorganic base,such as sodium carbonate or potassium carbonate, can be added untilreaching pH>7. The aqueous phase can be extracted with an organicsolvent such as dichloromethane. The organic phases can be gathered,dried over magnesium sulphate, filtered and concentrated under reducedpressure to give a compound of formula (IId).

The chemical structures and spectroscopic data of some compounds offormula (I) of the invention are illustrated respectively in thefollowing Table I and Table II.

TABLE I (I)

(Ia) 1

2

3

4

5

6

7

8

9

10

11

12

13

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

(Ib) 14

15

16

17

18

115

116

117

118

119

120

121

(Id) 32

33

34

35

122

TABLE II Ex Characterizations 1 ¹H NMR (300 MHz, CDCl₃) δ 8.61 (d, J =4.7 Hz, 1H), 7.66 (td, J = 7.7, 1.9 Hz, 1H), 7.60 (d, J = 16.1 Hz, 1H),7.52 (d, J = 8.6 Hz, 3H), 7.38 (d, J = 8.1 Hz, 1H), 7.33 (d, J = 7.4 Hz,1H), 7.25 (d, J = 7.7 Hz, 2H), 7.14 (td, J = 7.7, 1.9 Hz, 1H), 7.10 (d,J = 8.6 Hz, 2H), 7.08 (d, J = 16.1 Hz, 1H), 6.06 (s, 1H), 5.99 (s, 1H),3.49 (dd, J = 14.7, 5.9 Hz, 2H), 1.71 (dt, J = 13.4, 6.7 Hz, 1H), 1.52(dd, J = 14.7, 7.0 Hz, 2H), 0.97 (d, J = 6.6 Hz, 6H). 2 ¹H NMR (300 MHz,CDCl₃) δ 8.60 (d, J = 4.0 Hz, 1H), 7.79-7.48 (m, 6H), 7.37 (d, J = 7.9Hz, 1H), 7.22-7.03 (m, 6H), 6.14 (m, 1H), 6.00 (s, 1H), 3.48 (dd, J =13.8, 6.6 Hz, 2H), 1.70 (dt, J = 13.8, 6.6 Hz, 1H), 1.52 (dd, J = 13.8,6.6 Hz, 2H), 0.96 (d, J = 6.6 Hz, 6H). 3 ¹H NMR (300 MHz, CDCl₃) δ 8.58(d, J = 4.0 Hz, 1H), 7.86 (d, J = 16.3 Hz, 1H), 7.63 (td, J = 7.7, 1.7Hz, 1H), 7.57-7.51 (m, 2H), 7.42 (d, J = 7.9 Hz, 1H), 7.38-7.23 (m, 3H),7.15 (d, J = 16.3 Hz, 1H), 7.11-7.06 (m, 1H), 6.70 (dd, J = 8.3, 2.0 Hz,1H), 6.63 (d, J = 2.0 Hz, 1H), 6.13-6.00 (m, 2H), 3.86 (s, 3H), 3.48(dd, J = 14.6, 6.0 Hz, 2H), 1.68 (dt, J = 19.9, 6.6 Hz, 1H), 1.51 (dd, J= 14.7, 7.1 Hz, 2H), 0.96 (d, J = 6.6 Hz, 6H). 4 ¹H NMR (300 MHz, CDCl₃)δ 8.60 (d, J = 4.1 Hz, 1H), 7.69-7.49 (m, 5H), 7.37 (d, J = 7.8 Hz, 1H),7.32 (d, J = 7.6 Hz, 1H), 7.26-7.21 (m, 2H), 7.16-7.03 (m, 4H),6.10-5.99 (m, 1H), 5.96 (s, 1H), 3.48 (dd, J = 14.4, 6.0 Hz, 2H),1.82-1.67 (m, 5H), 1.51 (dd, J = 14.7, 7.0 Hz, 2H), 1.33- 1.15 (m, 4H),0.96 (dd, J = 20.1, 11.4 Hz, 2H). 5 ¹H NMR (300 MHz, CDCl₃) δ 8.59 (d, J= 4.0 Hz, 1H), 7.69-7.62 (m, 1H), 7.59 (d, J = 16.2 Hz, 1H), 7.54-7.48(m, 3H), 7.40-7.31 (m, 2H), 7.26-7.21 (m, 2H), 7.15-7.01 (m, 4H),6.17-6.07 (m, 1H), 5.97 (s, 1H), 3.28 (d, J = 6.3 Hz, 2H), 1.05-0.93 (m,10H). 6 ¹H NMR (300 MHz, d₆-DMSO) δ 8.59 (s, 1H), 8.54 (d, J = 3.8 Hz,1H), 8.40 (t, J = 5.5 Hz, 1H), 7.75 (td, J = 7.7, 1.6 Hz, 1H), 7.60 (dd,J = 8.5, 7.7 Hz, 2H), 7.56 (d, J = 8.5 Hz, 2H), 7.48 (d, J = 7.9 Hz,1H), 7.36-7.30 (m, 2H), 7.21 (ddd, J = 12.2, 5.5, 1.6 Hz, 2H), 7.14 (s,1H), 7.11 (d, J = 8.5 Hz, 2H), 3.26 (dd, J = 13.8, 6.2 Hz, 2H),1.85-1.72 (m, 3H), 1.66-1.42 (m, 6H), 1.18-0.99 (m, 2H). ¹³C NMR (75MHz, d₆-DMSO) δ 164.2, 153.6, 147.5, 141.6, 140.9, 134.8, 134.1, 130.1,127.2, 126.4, 126.0, 122.8, 119.9, 119.8, 117.8, 116.8, 114.5, 114.2,77.9, 35.5, 33.6, 30.3, 22.8 [M + H]⁺ = 412.3 7 ¹H NMR (300 MHz, CDCl₃)δ 8.61 (d, J = 4.0 Hz, 1H), 7.70-7.63 (m, 1H), 7.60 (d, J = 16.1 Hz,1H), 7.56-7.49 (m, 3H), 7.42-7.34 (m, 3H), 7.30-7.25 (m, 4H), 7.18-7.04(m, 4H), 6.05 (s, 1H), 3.01 (dd, J = 14.1, 6.7 Hz, 2H), 1.46-1.32 (m,3H), 0.86 (d, J = 6.6 Hz, 6H). 8 ¹H NMR (300 MHz, CDCl₃) δ 8.60 (d, J =4.3 Hz, 1H), 7.74-7.47 (m, 5H), 7.44-7.20 (m, 4H), 7.19-6.99 (m, 4H),6.26 (s, 1H), 6.00 (s, 1H), 3.55 (dd, J = 12.5, 6.4 Hz, 2H), 1.60-1.47(m, 2H), 0.84-0.67 (m, 1H), 0.59-0.43 (m, 2H), 0.21-0.07 (m, 2H). 9 ¹HNMR (300 MHz, d₆-DMSO) δ 8.56 (s, 1H), 8.53 (d, J = 3.9 Hz, 1H), 8.33(t, J = 5.5 Hz, 1H), 7.75 (td, J = 7.7, 1.8 Hz, 1H), 7.60 (d, J = 16.2Hz, 1H), 7.55 (d, J = 10.2 Hz, 2H), 7.48 (d, J = 7.9 Hz, 1H), 7.36-7.27(m, 2H), 7.25-7.17 (m, 2H), 7.14 (s, 1H), 7.10 (d, J = 8.8 Hz, 2H), 3.16(dd, J = 13.2, 6.5 Hz, 1H), 2.36-2.25 (dt, J = 15.5, 7.6 Hz, 1H),2.11-1.98 (m, 2H), 1.85-1.74 (m, 2H), 1.70-1.54 (m, 4H). [M + H]⁺ =398.0 10 ¹H NMR (300 MHz, d₆-DMSO) δ 9.44 (s, 1H), 8.55 (d, J = 4.6 Hz,1H), 8.08 (t, J = 5.9 Hz, 1H), 7.79-7.71 (m, 2H), 7.67 (d, J = 8.8 Hz,2H), 7.59 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 7.9 Hz, 1H), 7.40 (d, J =7.3 Hz, 1H), 7.21 (dd, J = 7.1, 5.2 Hz, 1H), 7.15 (d, J = 16.1 Hz, 1H),7.02 (d, J = 8.2 Hz, 1H), 3.42-3.33 (m, 2H), 1.92-1.70 (m, 3H),1.65-1.44 (m, 6H), 1.20-1.02 (m, 2H). 11 ¹H NMR (300 MHz, CDCl₃) δ 8.59(d, J = 4.0 Hz, 1H), 7.68 (d, J = 16.2 Hz, 1H), 7.69-7.61 (m, 1H), 7.54(d, J = 1.9 Hz, 1H), 7.53-7.47 (m, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.34(d, J = 7.6 Hz, 1H), 7.29 (dd, J = 5.5, 1.8 Hz, 1H), 7.13 (d, J = 16.4Hz, 1H), 7.15-7.11 (m, 1H), 6.84-6.76 (m, 2H), 6.10 (s, 1H), 6.06 (s,1H), 3.47 (dt, J = 7.4, 5.9 Hz, 2H), 1.77-1.68 (m, 4H), 1.51 (dd, J =14.7, 7.0 Hz, 2H), 1.40-1.14 (m, 4H), 1.04-0.86 (m, 2H). 12 ¹H NMR (300MHz, d₆-DMSO) δ 8.55 (d, J = 3.8 Hz, 1H), 8.34 (t, J = 5.5 Hz, 1H), 7.76(td, J = 1.1, 1.8 Hz, 1H), 7.71 (s, 1H), 7.60 (d, J = 16.1 Hz, 1H),7.53-7.40 (m, 3H), 7.41 (d, J = 8.4 Hz, 1H), 7.32-7.14 (m, 4H), 7.11(dd, J = 7.0, 2.3 Hz, 1H), 3.24 (dd, J = 13.9, 6.2 Hz, 2H), 2.26 (s,3H), 1.84-1.71 (m, 3H), 1.61-1.44 (m, 6H), 1.17-1.01 (m, 2H). [M + H]⁺ =426.4 13 ¹H NMR (300 MHz, d₆-DMSO) δ 8.55 (d, J = 4.0 Hz, 1H), 8.32 (t,J = 5.5 Hz, 1H), 7.81-7.72 (m, 1H), 7.71 (s, 1H), 7.60 (d, J = 16.0 Hz,1H), 7.53-7.46 (m, 3H), 7.41 (d, J = 8.6 Hz, 1H), 7.31- 7.17 (m, 5H),7.11 (d, J = 7.0 Hz, 1H), 3.25 (dd, J = 13.6, 6.5 Hz, 2H), 2.26 (s, 3H),1.61 (dt, J = 13.5, 6.8 Hz, 1H), 1.40 (dd, J = 14.4, 7.0 Hz, 2H), 0.90(d, J = 6.6 Hz, 6H). [M + H]⁺ = 400.3 91 ¹H NMR (300 MHz, CDCl₃) δ 8.58(d, J = 4.0 Hz, 1H), 7.92 (bs, 1H), 7.85 (d, J = 16.4 Hz, 1H), 7.67-7.59(m, 2H), 7.54 (d, J = 8.5 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.37-7.22(m, 3H), 7.14 (d, J = 16.4 Hz, 1H), 7.08 (d, J = 4.8 Hz, 1H), 6.70 (d, J= 8.3 Hz, 1H), 6.63 (d, J = 2.0 Hz, 1H), 5.95 (s, 1H), 3.86 (s, 3H),3.70-3.63 (m, 4H), 3.57 (dd, J = 11.3, 5.8 Hz, 2H), 2.60-2.52 (m, 2H),2.48 (s, 4H), 1.79 (dt, J = 12.3, 6.0 Hz, 2H). [M + H]⁺ = 473.4 92 ¹HNMR (300 MHz, CDCl₃) δ 8.58 (d, J = 4.0 Hz, 1H), 7.92 (s, 1H), 7.64 (td,J = 7.7, 1.7 Hz, 1H), 7.56 (d, J = 16.1 Hz, 1H), 7.49 (br s, 1H), 7.44(br s, 1H), 7.38 (br s, 1H), 7.35 (br s, 1H), 7.30 (d, J = 7.6 Hz, 2H),7.23 (d, J = 8.3 Hz, 1H), 7.13 (d, J = 12 Hz, 2H), 7.06 (d, J = 16.1 Hz,1H), 3.67- 3.61 (m, 4H), 3.55 (dd, J = 11.4, 5.7 Hz, 2H), 2.57-2.50 (m,2H), 2.46 (br s, 4H), 2.28 (s, 3H), 1.77 (dt, J = 12.0, 6.1 Hz, 2H). 93¹H NMR (300 MHz, CDCl₃) δ 8.71 (d, J = 1.9 Hz, 1H), 8.47 (dd, J = 4.7,1.4 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.54 (s, 1H), 7.48 (d, J = 8.5Hz, 2H), 7.40-7.37 (m, 2H), 7.31-7.23 (m, 2H), 7.12 (d, J = 16.7 Hz,1H), 7.11 (d, J = 8.2 Hz, 1H), 6.97 (d, J = 16.4 Hz, 1H), 6.05 (s, 1H),4.39 (t, J = 6.1 Hz, 1H), 3.00 (dd, J = 14.2, 6.6 Hz, 2H), 1.80-1.66 (m,3H), 1.59-1.41 (m, 5H), 1.12-0.96 (m, 2H). [M + H]⁺ = 448.3 94 ¹H NMR(400 MHz, d₆-DMSO) δ 8.57 (s, 1H), 8.54 (d, J = 3.8 Hz, 1H), 7.75 (td, J= 7.7, 1.8 Hz, 1H), 7.60 (d, J = 16.1 Hz, 1H), 7.56 (d, J = 8.6 Hz, 2H),7.49 (d, J = 7.9 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 7.23-7.18 (m, 2H),7.12 (d, J = 16.0 Hz, 1H), 7.11 (d, J = 8.6 Hz, 2H), 7.08-7.06 (m, 1H),6.86 (d, J = 7.5 Hz, 1H), 4.56 (br s, 1H), 3.78 (br s, 1H), 3.08 (br s,1H), 2.80 (br s, 1H), 2.71-2.58 (m, 1H), 1.87 (br s, 2H), 1.46-1.36 (m,2H). 95 ¹H NMR (300 MHz, d₆-DMSO) δ 8.74 (s, 1H), 8.65 (s, 1H), 8.57 (s,1H), 8.43 (d, J = 2.4 Hz, 1H), 8.38 (t, J = 5.4 Hz, 1H), 7.72 (d, J =16.2 Hz, 1H), 7.59 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 5.7 Hz, 2H),7.29-7.22 (m, 1H), 7.18 (d, J = 16.1 Hz, 1H), 7.11 (d, J = 8.5 Hz, 2H),3.26 (dd, J = 13.5, 6.6 Hz, 2H), 1.69-1.54 (m, 1H), 1.41 (dd, J = 14.2,7.0 Hz, 2H), 0.90 (d, J = 6.6 Hz, 6H). [M + H]⁺ = 387.0 96 ¹H NMR (300MHz, d₆-DMSO) δ 8.74 (s, 1H), 8.65 (s, 1H), 8.57 (s, 1H), 8.43-8.38 (m,2H), 7.72 (d, J = 16.4 Hz, 1H), 7.59 (d, J = 7.7 Hz, 3H), 7.33 (br s,1H), 7.26-7.23 (m, 1H), 7.18 (d, J = 16.4 Hz, 1H), 7.11 (d, J = 8.3 Hz,2H), 3.25 (dd, J = 13.3, 6.6 Hz, 2H), 1.82-1.73 (m, 3H), 1.64- 1.41 (m,6H), 1.09 (t, J = 6.9 Hz, 2H). 97 ¹H NMR (300 MHz, CDCl₃) δ 8.59 (d, J =3.8 Hz, 1H), 7.65 (t, J = 7.5 Hz, 1H), 7.58 (d, J = 16.0 Hz, 1H), 7.50(d, J = 8.5 Hz, 2H), 7.36 (d, J = 7.9 Hz, 1H), 7.32-7.26 (m, 1H),7.14-7.10 (m, 2H), 7.07 (d, J = 8.5 Hz, 2H), 7.05 (d, J = 16.2 Hz, 1H),6.94 (d, J = 7.5 Hz, 1H), 5.92 (s, 1H), 3.71 (br s, 2H), 3.38 (br s,2H), 1.45 (br s, 2H), 1.32 (br s, 2H), 1.00 (s, 6H). 98 ¹H NMR (300 MHz,CDCl₃) δ 8.58 (d, J = 3.9 Hz, 1H), 7.67-7.61 (m, 1H), 7.58 (d, J = 16.1Hz, 1H), 7.49 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 7.9 Hz, 1H), 7.31-7.22(m, 2H), 7.12 (dd, J = 5.3, 3.6 Hz, 3H), 7.06 (d, J = 8.5 Hz, 2H), 7.04(d, J = 16.2 Hz, 1H), 6.93 (d, J = 7.5 Hz, 1H), 6.06 (s, 1H), 3.70 (bs,2H), 3.37 (bs, 2H), 1.74-1.63 (m, 8H), 1.56-1.38 (m, 4H). 99 ¹H NMR (300MHz, CDCl₃) δ 8.60 (d, J = 4.2 Hz, 1H), 7.71-7.62 (m, 2H), 7.58-7.51 (m,3H), 7.37 (d, J = 8.1 Hz, 2H), 7.21 (d, J = 9.0 Hz, 1H), 7.14 (d, J =6.6 Hz, 2H), 7.13 (s, 1H), 7.08 (d, J = 16.2 Hz, 2H), 6.04 (s, 1H), 2.67(d, J = 7.0 Hz, 2H), 2.04 (dt, J = 17.0, 6.9 Hz, 1H), 0.98 (d, J = 6.6Hz, 6H). 100 ¹H NMR (400 MHz, d₆-DMSO) δ 8.74 (d, J = 2.1 Hz, 1H), 8.72(s, 1H), 8.53 (s, 1H), 8.42 (dd, J = 4.7, 1.5 Hz, 1H), 8.01 (dt, J =8.0, 1.8 Hz, 1H), 7.61 (t, J = 2.1 Hz, 1H), 7.56 (d, J = 8.6 Hz, 2H),7.44 (t, J = 8.1 Hz, 1H), 7.38 (dd, J = 7.9, 4.8 Hz, 1H), 7.33 (d, J =16.5 Hz, 1H), 7.29 (dd, J = 8.0, 1.4 Hz, 1H), 7.18 (d, J = 8.6 Hz, 2H),7.15 (dd, J = 8.0, 1.4 Hz, 1H), 7.12 (d, J = 16.5 Hz, 1H), 2.59 (d, J =6.9 Hz, 2H), 1.97 (sextuplet, J = 13.5, 6.7 Hz, 1H), 0.94 (d, J = 6.6Hz, 6H). 101 ¹H NMR (300 MHz, CDCl₃) δ 8.70 (d, J = 2.1 Hz, 1H), 8.46(dd, J = 4.6, 1.4 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.53 (s, 1H), 7.46(d, J = 8.5 Hz, 2H), 7.36-7.20 (m, 4H), 7.12 (d, J = 16.3 Hz, 1H), 7.09(d, J = 8.6 Hz, 2H), 6.95 (d, J = 16.2 Hz, 1H), 6.03 (s, 1H), 5.95 (s,1H), 3.47 (dd, J = 14.5, 5.8 Hz, 2H), 1.76-1.63 (m, 1H), 1.51 (dd, J =14.7, 7.1 Hz, 2H), 0.96 (d, J = 6.6 Hz, 6H). 102 ¹H NMR (400 MHz,d₆-DMSO) δ 8.74 (bs, 2H), 8.42 (dd, J = 4.7, 1.5 Hz, 1H), 8.01 (dt, J =8.0, 1.8 Hz, 1H), 7.56 (d, J = 8.6 Hz, 2H), 7.52-7.49 (m, 2H), 7.45 (t,J = 7.9 Hz, 1H), 7.38 (dd, J = 8.0, 4.8 Hz, 1H), 7.34 (d, J = 16.7 Hz,1H), 7.29 (dd, J = 8.0, 1.8 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 7.14 (d,J = 8.6 Hz, 2H), 7.12 (d, J = 16.5 Hz, 1H), 2.78 (dd, J = 14.5, 7.1 Hz,2H), 1.58 (q, J = 6.7 Hz, 1H), 1.27 (dd, J = 14.5, 7.0 Hz, 2H), 0.80 (d,J = 6.6 Hz, 6H). 103 ¹H NMR (300 MHz, CDCl₃) δ 8.70 (d, J = 1.7 Hz, 1H),8.46 (dd, J = 4.7, 1.4 Hz, 1H), 7.82 (d, J = 7.9 Hz, 1H), 7.53 (s, 1H),7.46 (d, J = 8.5 Hz, 2H), 7.36-7.21 (m, 4H), 7.12 (d, J = 16.1 Hz, 1H),7.09 (d, J = 8.5 Hz, 2H), 6.95 (d, J = 16.4 Hz, 1H), 6.07 (s, 1H), 5.95(s, 1H), 3.46 (dd, J = 14.4, 6.1 Hz, 2H), 1.89-1.76 (m, 3H), 1.68-1.48(m, 6H), 1.22-1.08 (m, 2H). 104 ¹H NMR (300 MHz, CDCl₃) δ 8.70 (d, J =1.6 Hz, 1H), 8.46 (dd, J = 4.7, 1.3 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H),7.54 (s, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.38-7.22 (m, 4H), 7.12 (d, J =16.5 Hz, 1H), 7.09 (d, J = 8.5 Hz, 2H), 6.95 (d, J = 16.4 Hz, 1H), 6.14(bs, 1H), 6.00 (s, 1H), 3.28 (d, J = 6.4 Hz, 2H), 0.99 (s, 9H) 105 ¹HNMR (300 MHz, CDCl₃) δ 8.70 (d, J = 1.7 Hz, 1H), 8.46 (dd, J = 4.5, 1.1Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.53 (bs, 1H), 7.45 (d, J = 8.5 Hz,2H), 7.36-7.20 (m, 4H), 7.12 (d, J = 16.3 Hz, 1H), 7.09 (d, J = 8.4 Hz,2H), 6.94 (d, J = 16.4 Hz, 1H), 6.05 (bs, 1H), 6.00 (s, 1H), 3.47 (dd, J= 13.7, 6.7 Hz, 2H), 1.80-1.63 (m, 5H), 1.51 (dd, J = 14.5, 7.0 Hz, 2H),1.27-1.19 (m, 4H), 1.00-0.90 (m, 2H). 106 ¹H NMR (400 MHz, d₆-DMSO) δ8.79 (s, 1H), 8.55 (d, J = 3.8 Hz, 1H), 7.76 (td, J = 7.7, 1.8 Hz, 1H),7.62 (d, J = 16.0 Hz, 1H), 7.60 (d, J = 8.6 Hz, 2H), 7.56 (t, J = 5.8Hz, 1H), 7.52-7.49 (m, 2H), 7.45 (t, J = 7.9 Hz, 1H), 7.31 (dd, J = 7.9,1.9 Hz, 1H), 7.21 (dd, J = 9.1, 4.2 Hz, 2H), 7.19 (d, J = 15.3 Hz, 1H),7.15 (d, J = 8.5 Hz, 2H), 3.53-3.48 (m, 4H), 2.81 (dd, J = 12.8, 6.8 Hz,2H), 2.26-2.19 (m, 6H), 1.52 (p, J = 7.0 Hz, 2H). 107 ¹H NMR (300 MHz,CDCl₃) δ 8.58 (d, J = 3.9 Hz, 1H), 8.29 (d, J = 5.2 Hz, 1H), 8.20 (t, J= 4.6 Hz, 1H), 7.64 (t, J = 7.7 Hz, 1H), 7.58 (d, J = 16.0 Hz, 1H), 7.53(d, J = 8.7 Hz, 2H), 7.45 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 8.9 Hz, 2H),7.14-7.10 (m, 1H), 7.06 (d, J = 16.1 Hz, 1H), 6.96 (dd, J = 5.2, 1.1 Hz,1H), 3.65-3.59 (m, 4H), 3.54 (dd, J = 11.2, 5.7 Hz, 2H), 2.55-2.49 (m,2H), 2.48- 2.41 (m, 4H), 1.76 (dt, J = 11.8, 5.9 Hz, 2H). 108 ¹H NMR(400 MHz, d₆-DMSO) δ 9.43 (s, 1H), 8.55 (d, J = 3.8 Hz, 1H), 8.16 (t, J= 5.9 Hz, 1H), 7.80-7.73 (m, 2H), 7.67 (t, J = 6.4 Hz, 2H), 7.64-7.60(m, 3H), 7.51 (d, J = 7.9 Hz, 1H), 7.41 (d, J = 7.3 Hz, 1H), 7.22 (dd, J= 7.5, 4.8 Hz, 1H), 7.16 (d, J = 16.0 Hz, 1H), 7.03 (d, J = 8.3 Hz, 1H),3.54-3.49 (m, 4H), 3.39 (q, J = 6.6 Hz, 2H), 2.39-2.34 (m, 6H), 1.73 (p,J = 6.8 Hz, 2H). 109 ¹H NMR (300 MHz, CDCl₃) δ 8.60-8.57 (m, 2H), 8.28(d, J = 52 Hz, 1H), 7.78 (bs, 1H), 7.66- 7.60 (m, 1H), 7.57 (d, J = 16.2Hz, 1H), 7.51 (s, 4H), 7.36 (d, J = 7.0 Hz, 2H), 7.14-7.10 (m, 1H), 7.06(d, J = 16.1 Hz, 1H), 7.00 (dd, J = 52, 1.0 Hz, 1H), 3.53 (dd, J = 10.7,5.4 Hz, 2H), 3.06 (bs, 1H), 2.54-2.39 (m, 10H), 1.75 (q, J = 5.7 Hz,2H). 110 ¹H NMR (300 MHz, CDCl₃) δ 8.56 (d, J = 3.9 Hz, 1H), 8.14 (t, J= 5.8 Hz, 1H), 7.66-7.56 (m, 3H), 7.51 (d, J = 8.5 Hz, 2H), 7.38-7.31(m, 3H), 7.22 (s, 1H), 7.10 (dd, J = 7.9, 4.3 Hz, 1H), 7.06 (d, J = 16.1Hz, 1H), 6.96 (dd, J = 6.7, 2.4 Hz, 1H), 3.49 (dd, J = 12.6, 6.4 Hz,2H), 2.48-2.36 (m, 10H), 2.19 (s, 3H), 1.77 (dt, J = 13.3, 6.5 Hz, 2H).111 ¹H NMR (300 MHz, CDCl₃) δ 8.59 (d, J = 3.8 Hz, 1H), 7.90 (s, 1H),7.65 (td, J = 7.7, 1.8 Hz, 1H), 7.61-7.55 (m, 2H), 7.51 (d, J = 8.5 Hz,2H), 7.39-7.28 (m, 3H), 7.25-7.20 (m, 1H), 7.14-7.11 (m, 1H), 7.08 (d, J= 8.5 Hz, 2H), 7.05 (d, J = 15.9 Hz, 1H), 5.97 (s, 1H), 3.69-3.63 (m,4H), 3.57 (dd, J = 11.3, 5.8 Hz, 2H), 2.59-2.51 (m, 2H), 2.48 (s, 4H),1.79 (dt, J = 12.2, 6.3 Hz, 2H). 112 ¹H NMR (400 MHz, d₆-DMSO) δ 8.56(s, 1H), 8.54 (d, J = 4.8 Hz, 1H), 8.45 (t, J = 5.4 Hz, 1H), 7.75 (td, J= 7.7, 1.8 Hz, 1H), 7.60 (d, J = 15.8 Hz, 1H), 7.59 (bs, 1H), 7.56 (d, J= 8.6 Hz, 2H), 7.49 (d, J = 7.9 Hz, 1H), 7.34 (t, J = 7.7 Hz, 1H),7.32-7.30 (m, 1H), 7.25-7.23 (m, 1H), 7.22- 7.19 (m, 1H), 7.12 (d, J =16.0 Hz, 1H), 7.11 (d, J = 8.6 Hz, 2H), 3.27 (dd, J = 12.7, 6.9 Hz, 2H),2.36 (bs, 6H), 1.73-1.63 (m, 2H), 1.53-1.47 (m, 4H), 1.43-1.38 (m, 2H).113 ¹H NMR (400 MHz, d₆-DMSO) δ 8.56 (s, 1H), 8.54 (d, J = 4.8 Hz, 1H),8.45 (t, J = 5.4 Hz, 1H), 7.75 (td, J = 7.7, 1.8 Hz, 1H), 7.60 (d, J =15.8 Hz, 1H), 7.59 (bs, 1H), 7.56 (d, J = 8.6 Hz, 2H), 7.49 (d, J = 7.9Hz, 1H), 7.34 (t, J = 7.7 Hz, 1H), 7.32-7.30 (m, 1H), 7.25-7.23 (m, 1H),7.22- 7.19 (m, 1H), 7.12 (d, J = 16.0 Hz, 1H), 7.11 (d, J = 8.6 Hz, 2H),3.27 (dd, J = 12.6, 6.8 Hz, 2H), 2.42-2.25 (m, 10H), 2.15 (s, 3H), 1.67(p, J = 7.0 Hz, 2H). 114 ¹H NMR (300 MHz, CDCl₃) δ 8.59 (d, J = 3.8 Hz,1H), 7.96 (s, 1H), 7.65 (t, J = 7.5 Hz, 1H), 7.58 (d, J = 16.0 Hz, 1H),7.50 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 7.9 Hz, 1H), 7.32-7.26 (m, 1H),7.14- 7.10 (m, 2H), 7.07 (d, J = 8.5 Hz, 2H), 7.05 (d, J = 16.2 Hz, 1H),6.94 (d, J = 7.5 Hz, 1H), 5.92 (s, 1H), 3.90 (s, 2H), 2.64 (q, J = 7.1Hz, 5H), 1.13 (t, J = 7.1 Hz, 6H). 14 ¹H NMR (300 MHz, CDCl₃) δ 8.46 (s,1H), 8.38 (d, J = 8.2 Hz, 1H), 8.31 (d, J = 4.2 Hz, 1H), 7.84 (d, J =8.4 Hz, 2H), 7.75 (t, J = 7.9 Hz, 1H), 7.59 (s, 1H), 7.42-7.28 (m, 5H),7.09 (d, J = 8.3 Hz, 2H), 7.07-7.00 (m, 2H), 6.16 (s, 1H), 6.07 (s, 1H),3.48 (dd, J = 13.7, 6.7 Hz, 2H), 1.75-1.64 (m, 1H), 1.52 (dd, J = 14.5,7.1 Hz, 2H), 0.96 (d, J = 6.6 Hz, 6H). [M + H]⁺ = 403.1 15 ¹H NMR (300MHz, d₆-DMSO) δ 10.46 (s, 1H), 8.83 (s, 1H), 8.44 (t, J = 5.5 Hz, 1H),8.37 (d, J = 3.8 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 8.7 Hz,2H), 7.87-7.77 (m, 1H), 7.65 (s, 1H), 7.45-7.36 (m, 2H), 7.30 (dt, J =6.5, 2.2 Hz, 1H), 7.15 (d, J = 5.5 Hz, 1H), 7.11 (d, J = 8.7 Hz, 2H),3.26 (dd, J = 13.7, 6.4 Hz, 2H), 1.87-1.72 (m, 3H), 1.67-1.40 (m, 6H),1.07 (m, 2H). ¹³C NMR (75 MHz, d₆-DMSO) 164.2, 163.5, 150.8, 146.1,145.3, 140.1, 136.2, 134.3, 128.1, 127.5, 122.3, 119.3, 118.1, 117.6,117.5, 115.7, 112.8, 112.7, 35.7, 33.7, 30.5, 23.0 [M + H]⁺ = 429.1 16¹H NMR (300 MHz, d₆-DMSO) δ 10.46 (s, 1H), 8.83 (s, 1H), 8.42-8.37 (m,2H), 8.19 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 8.7 Hz, 2H), 7.82 (t, J =8.8 Hz, 1H), 7.64 (s, 1H), 7.42-7.35 (m, 2H), 7.32- 7..29 (m 1H),7.17-7.13 (m, 1H), 7.10 (d, J = 8.6 Hz, 2H), 3.28 (dd, J = 13.3, 6.8 Hz,2H), 1.78- 1.57 (m, 5H), 1.43 (dd, J = 14.2, 6.9 Hz, 2H), 1.34-1.12 (m,4H), 0.99-0.82 (m, 2H). 17 ¹H NMR (300 MHz, d₆-DMSO) δ 10.92 (s, 1H),8.91 (d, J = 8.8 Hz, 2H), 8.68 (d, J = 5.8 Hz, 1H), 8.44-8.41 (m, 1H),8.21 (dd, J = 5.9, 1.3 Hz, 2H), 7.98 (d, J = 8.8 Hz, 2H), 7.66 (s, 1H),7.47- 7.36 (m, 2H), 7.31 (d, J = 7.2 Hz, 1H), 7.11 (d, J = 8.8 Hz, 2H),3.27 (dd, J = 13.7, 6.5 Hz, 2H), 1.84-1.73 (m, 3H), 1.64-1.44 (m, 6H),1.17-1.04 (m, 2H). [M + H]⁺ = 430.0 18 ¹H NMR (300 MHz, d₆-DMSO) δ 10.68(s, 1H), 8.82 (s, 1H), 8.70 (d, J = 4.8 Hz, 2H), 8.39 (t, J = 5.5 Hz,1H), 7.90 (d, J = 8.7 Hz, 2H), 7.64 (s, 1H), 7.42-7.34 (m, 2H),7.32-7.29 (m, 1H), 7.21 (t, J = 4.8 Hz, 1H), 7.09 (d, J = 8.7 Hz, 2H),3.27 (dd, J = 13.8, 6.4 Hz, 2H), 1.62 (dt, J = 13.3, 6.7 Hz, 1H), 1.42(dd, J = 14.4, 6.9 Hz, 2H), 0.90 (d, J = 6.6 Hz, 6H). [M + H]⁺ = 404.0115 ¹H NMR (400 MHz, d₆-DMSO) δ 9.96 (s, 1H), 7.78-7.67 (m, 4H), 7.57(d, J = 2.0 Hz, 1H), 7.33 (t, J = 7.9 Hz, 2H), 7.23 (d, J = 8.5 Hz, 1H),7.16 (t, J = 8.1 Hz, 1H), 7.07 (t, J = 7.4 Hz, 1H), 6.74- 6.68 (m, 1H),6.67 (t, J = 2.1 Hz, 1H), 6.48 (dd, J = 8.1, 2.1 Hz, 1H), 3.91 (t, J =6.5 Hz, 2H), 2.04- 1.92 (m, 1H), 1.75-1.57 (m, 7H), 1.35-1.09 (m, 6H),1.04-0.95 (m, 2H), 0.88 (q, J = 10.1, 9.5 Hz, 2H), 0.76-0.67 (m, 2H).¹³C NMR (151 MHz, d₆-DMSO) δ 165.6, 160.0, 146.2, 144.9, 139.9, 131.8,130.2, 128.9, 126.8, 126.7, 126.4, 123.7, 120.9, 116.2, 111.4, 107.5,105.3, 68.0, 37.2, 33.7, 33.3, 26.6, 26.6, 26.3, 11.6, 7.8 [M + H]⁺ =469.2 116 ¹H NMR (300 MHz, CDCl₃) δ 9.70 (s, 1H), 8.66 (d, J = 4.6 Hz,3H), 7.74-7.71 (m, 2H), 7.52 (d, J = 8.4 Hz, 1H), 7.45 (t, J = 7.8 Hz,2H), 7.36 (t, J = 7.8 Hz, 1H), 7.04 (t, J = 4.4 Hz, 1H), 6.91 (t, J =7.5 Hz, 1H), 6.11 (d, J = 5.1 Hz, 1H), 3.45 (dd, J = 14.7, 7.0 Hz, 2H),1.97-1.85 (m, 1H), 1.73- 1.62 (m, 1H), 1.51 (dd, J = 14.7, 7.0 Hz, 2H),1.12 (q, J = 5.2 Hz, 2H), 0.95 (d, J = 6.6 Hz, 6H), 0.71 (q, J = 5.2 Hz,2H). [M + H]⁺ = 444.4 117 ¹H NMR (300 MHz, CDCl₃) δ 9.65 (s, 1H), 8.67(d, J = 4.9 Hz, 2H), 8.55 (s, 1H), 7.75-7.72 (m, 2H), 7.53 (d, J = 8.3Hz, 1H), 7.45 (t, J = 7.1 Hz, 2H), 7.39 (t, J = 8.0 Hz, 1H), 7.05 (t, J= 4.9 Hz, 1H), 6.93 (t, J = 7.3 Hz, 1H), 6.42 (t, J = 5.7 Hz, 1H), 3.72(dd, J = 12.6, 6.2 Hz, 2H), 2.56-2.39 (m, 2H), 1.97-1.85 (m, 1H),1.17-1.08 (q, J = 5.7 Hz, 2H), 0.73 (q, J = 5.7 Hz, 2H). [M + H]⁺ =470.3 118 ¹H NMR (300 MHz, CDCl₃) δ 8.83 (s, 1H), 8.35 (d, J = 8.3 Hz,1H), 8.24 (d, J = 4.8 Hz, 1H), 8.07 (t, J = 4.3 Hz, 1H), 7.77 (d, J =8.5 Hz, 2H), 7.75-7.65 (m, 2H), 7.36-7.26 (m, 3H), 7.09-6.96 (m, 4H),3.67-3.60 (m, 4H), 3.54 (dd, J = 11.1, 5.6 Hz, 2H), 2.54-2.47 (m, 2H),2.44 (bs, 4H), 1.76 (dt, J = 11.6, 5.9 Hz, 2H). 119 ¹H NMR (300 MHz,CDCl₃) δ 8.91 (s, 1H), 8.62 (bs, 1H), 8.36 (d, J = 8.3 Hz, 1H), 8.23 (d,J = 4.1 Hz, 1H), 7.79 (d, J = 8.6 Hz, 2H), 7.74-7.64 (m, 2H), 7.43-7.38(m, 1H), 7.35-7.27 (m, 2H), 7.10-6.97 (m, 4H), 3.51 (dd, J = 10.7, 5.4Hz, 2H), 2.50-2.43 (m, 2H), 2.38 (s, 4H), 1.74 (dt, J = 11.3, 5.8 Hz,2H), 1.56-1.45 (m, 4H), 1.38 (d, J = 4.4 Hz, 2H). 120 ¹H NMR (300 MHz,CDCl₃) δ 8.83 (s, 1H), 8.35 (d, J = 8.3 Hz, 1H), 8.24 (d, J = 4.8 Hz,1H), 8.07 (t, J = 4.3 Hz, 1H), 7.77 (d, J = 8.5 Hz, 2H), 7.75-7.65 (m,2H), 7.36-7.26 (m, 3H), 7.09-6.96 (m, 4H), 3.54 (dd, J = 11.1, 5.6 Hz,2H), 2.60-2.47 (m, 6H), 2.45-2.36 (m, 4H), 2.22 (s, 3H), 1.76 (dt, J =11.6, 5.9 Hz, 2H). 121 ¹H NMR (300 MHz, d₆-DMSO) δ 10.47 (s, 1H), 8.99(s, 1H), 8.65 (s, 1H), 8.36 (d, J = 4.0 Hz, 1H), 8.17 (d, J = 8.4 Hz,1H), 7.99 (d, J = 8.6 Hz, 2H), 7.80 (t, J = 7.0 Hz, 1H), 7.68 (s, 1H),7.50 (d, J = 7.9 Hz, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.24 (d, J = 7.5 Hz,1H), 7.18 (d, J = 8.8 Hz, 2H), 7.15-7.08 (m, 1H), 5.31 (t, J = 5.6 Hz,1H), 4.60 (d, J = 5.6 Hz, 2H). [M + H]⁺ = 470.3 32 ¹H NMR (300 MHz,CDCl₃) δ 9.96 (s, 1H), 8.61 (d, J = 4.7 Hz, 1H), 8.29 (d, J = 7.8 Hz,1H), 7.90 (td, J = 7.7, 1.4 Hz, 1H), 7.69 (d, J = 8.7 Hz, 2H), 7.48 (dd,J = 7.5, 4.9 Hz, 1H), 7.43 (s, 1H), 7.25 (d, J = 8.5 Hz, 1H), 7.21-7.14(m, 2H), 7.11 (d, J = 8.7 Hz, 2H), 6.19 (s, 1H), 5.97 (s, 1H), 3.45 (dd,J = 13.9, 6.6 Hz, 2H), 1.67 (dt, J = 13.4, 6.6 Hz, 1H), 1.49 (dd, J =14.8, 7.0 Hz, 2H), 0.94 (d, J = 6.6 Hz, 6H). [M + H]⁺ = 403.1 33 ¹H NMR(300 MHz, CDCl₃) δ 9.98 (s, 1H), 8.62 (d, J = 4.5 Hz, 1H), 8.30 (d, J =7.7 Hz, 1H), 7.91 (td, J = 7.7, 1.5 Hz, 1H), 7.72 (d, J = 8.7 Hz, 2H),7.49 (dd, J = 6.9, 5.2 Hz, 1H), 7.43 (s, 1H), 7.33- 7.25 (m, 2H), 7.19(d, J = 7.7 Hz, 2H), 7.15 (d, J = 8.7 Hz, 2H), 6.11 (s, 1H), 5.82 (s,1H), 3.27 (d, J = 6.4 Hz, 2H), 0.98 (s, 9H). [M + H]⁺ = 403.1 34 ¹H NMR(300 MHz, d₆-DMSO) δ 10.59 (s, 1H), 8.74 (d, J = 4.4 Hz, 1H), 8.52 (s,1H), 8.15 (d, J = 7.7 Hz, 1H), 8.06 (t, J = 7.1 Hz, 1H), 7.84 (d, J =8.8 Hz, 2H), 7.71-7.63 (m, 1H), 7.48 (t, J = 5.7 Hz, 1H), 7.43-7.35 (m,2H), 7.20 (d, J = 9.6 Hz, 1H), 7.13 (d, J = 8.9 Hz, 3H), 2.75 (dd, J =13.0, 6.7 Hz, 2H), 1.56 (dt, J = 13.9, 7.0 Hz, 1H), 1.25 (dd, J = 14.2,7.2 Hz, 2H), 0.79 (d, J = 6.6 Hz, 6H). [M + H]⁺ = 439.1 35 ¹H NMR (300MHz, d₆-DMSO) δ 10.54 (s, 1H), 8.74 (d, J = 4.4 Hz, 1H), 8.36 (t, J =5.4 Hz, 1H), 8.29 (s, 1H), 8.16 (d, J = 7.7 Hz, 1H), 8.07 (td, J = 7.7,1.5 Hz, 1H), 7.82 (d, J = 8.8 Hz, 2H), 7.71- 7.62 (m, 1H), 7.51 (s, 1H),7.34-7.20 (m, 2H), 7.16-7.10 (m, 3H), 3.25 (dd, J = 13.4, 6.5 Hz, 2H),1.82-1.72 (m, 3H), 1.68-1.45 (m, 6H), 1.12-1.08 (m, 2H). ¹³C NMR (75MHz, d₆-DMSO) δ 164.9, 160.5, 148.7, 146.9, 142.6, 137.6, 136.6, 134.5,130.0, 127.6, 125.3, 120.8, 120.0, 116.7, 116.4, 116.1, 113.1, 35.9,34.0, 30.7, 23.2 [M + H]⁺ = 429.1 122 ¹H NMR (300 MHz, CDCl₃) δ 10.01(s, 1H), 8.63 (d, J = 4.7 Hz, 1H), 8.31 (d, J = 7.7 Hz, 1H), 7.92 (td, J= 7.9, 1.9 Hz, 1H), 7.76 (d, J = 8.7 Hz, 2H), 7.67 (s, 1H), 7.49 (ddd, J= 7.5, 4.9, 1.1 Hz, 1H), 7.41 (t, J = 2.2 Hz, 1H), 7.35 (t, J = 8.1 Hz,2H), 7.20 (d, J = 8.9 Hz, 2H), 7.18-7.14 (m, 1H), 7.03 (dd, J = 8.5, 2.0Hz, 1H), 5.90 (s, 1H), 2.66 (d, J = 6.8 Hz, 2H), 2.03 (dt, J = 13.3, 6.8Hz, 1H), 0.98 (d, J = 6.7 Hz, 6H).

The following examples are provided as illustrations and in no way limitthe scope of this invention.

The following examples illustrate in detail the preparation of somecompounds according to the invention. The structures of the productsobtained have been confirmed by NMR analyses.

EXAMPLES Example 1: Compound (6) in Table I

According to procedure (B), 2-vinylpyridine (2.32 mL, 22 mmoles, 1.1eq.) was placed in N,N-dimethylformamide (20 mL) with1-bromo-4-nitrobenzene (4 g, 20 mmoles, 1 eq.), NaOAc (3.3 g, 40 mmoles,2 eq.), Pd(OAc)_(z)(450 mg, 2 mmoles, 10 mol %), PPh₃ (525 mg, 2 mmoles,10 mol %). The reaction mixture was heated at 135° C. and stirred for 16hours under an inert atmosphere of argon. Upon cooling to roomtemperature, the reaction mixture was concentrated under reducedpressure and the resulting residue was partitioned between ethyl acetateand water. Upon decantation, the aqueous phase was further extractedwith dichloromethane. The organic phases were further washed with water,dried over MgSO₄, filtered, gathered and concentrated under reducedpressure to give (E)-2-[2-(4-nitrophenyl)ethenyl]pyridine (1.9 g, 42%).

¹H NMR (300 MHz, CDCl₃) δ 8.65 (d, J=4.1 Hz, 1H), 8.24 (d, J=9.0 Hz,2H), 7.75-7.69 (m, 4H), 7.42 (d, J=7.8 Hz, 1H), 7.30 (d, J=16.2 Hz, 1H),7.27-7.20 (m, 1H).

According to procedure (C), (E)-2-[2-(4-nitrophenyl)ethenyl]pyridine(1.9 g, 8.4 mmoles, 1 eq.) and tin (II) chloride dihydrate (9.5 g, 42mmoles, 5 eq.) were placed in EtOH (84 mL). The reaction mixture washeated at 60° C. and stirred for 88 hours under an inert atmosphere ofargon. The reaction mixture was then concentrated under reduced pressureand the resulting residue was diluted with ethyl acetate. The organicphase was washed with a 1N NaOH aqueous solution then with a saturatedaqueous solution of brine, dried over MgSO₄, filtered and concentratedunder reduced pressure to afford (E)-4-[2-(pyridin-2-yl)ethenyl]aniline(1.59 g, 96%).

¹H NMR (300 MHz, CDCl₃) δ 8.56 (d, J=4.5 Hz, 1H), 7.62 (td, J=7.9, 1.8Hz, 1H), 7.53 (d, J=16.1 Hz, 1H), 7.40 (d, J=8.5 Hz, 2H), 7.33 (d, J=7.9Hz, 1H), 7.09 (dd, J=7.0, 4.5 Hz, 1H), 6.98 (d, J=16.1 Hz, 1H), 6.68 (d,J=8.5 Hz, 2H), 3.80 (s, 2H).

2-Cyclopentylethan-1-amine hydrochloride (3.0 g, 19.1 mmoles, 1.1 eq.)was placed in a 3N NaOH aqueous solution (13 mL) and dichloromethane(3.2 mL) was added to the solution. The reaction mixture was cooled downto 0° C. with an ice bath and a solution of 3-bromobenzoyl chloride (2.3mL, 17.4 mmoles, 1 eq.) in dichloromethane (5.5 mL) was added dropwise.The reaction mixture was then stirred at room temperature for 18 hoursunder an inert atmosphere of argon. Upon decantation, the organic phasewas washed with a saturated aqueous solution of brine, dried over MgSO₄,filtered and concentrated under reduced pressure to afford3-bromo-N-(2-cyclopentylethyl)benzamide (5.1 g, 99%).

¹H NMR (300 MHz, CDCl₃) δ 7.89 (t, J=1.7 Hz, 1H), 7.67 (d, J=8.0 Hz,1H), 7.62 (d, J=8.0 Hz, 1H), 7.30 (t, J=8.0 Hz, 1H), 6.07 (s, 1H), 3.46(dt, J=7.4, 5.9 Hz, 2H), 1.93-1.77 (m, 3H), 1.67-1.52 (m, 6H), 1.25-1.06(m, 2H).

According to procedure (A), a reaction mixture of3-bromo-N-(2-cyclopentylethyl)benzamide (755 mg, 2.55 mmoles, 1 eq.),(E)-4-[2-(pyridin-2-yl)ethenyl]aniline (500 mg, 2.55 mmoles, 1 eq.),Pd₂(dba)₃ (233 mg, 255 μmoles, 10 mol %), XPhos (243 mg, 510 μmoles, 20mol %) and K₂CO₃ (1.41 g, 10.2 mmoles, 4 eq.) in t-BuOH (10.2 mL) washeated at 90° C. and stirred for 20 hours under an inert atmosphere ofargon. The reaction mixture was then concentrated under reduced pressureand the resulting residue was diluted with dichloromethane. The organicphase was washed with a saturated aqueous solution of brine, dried overMgSO₄, filtered and concentrated under reduced pressure. The resultingresidue was purified by column chromatography on silica gel to afford afraction which, after trituration in diethyl ether, gave(E)-N-(2-cyclopentylethyl)-3-((4-(2-(pyridin-2-yl)vinyl)phenyl)amino)benzamide(6) (613 mg, 58%).

¹H NMR (300 MHz, d₆-DMSO) δ 8.59 (s, 1H), 8.54 (d, J=3.8 Hz, 1H), 8.40(t, J=5.5 Hz, 1H), 7.75 (td, J=7.7, 1.6 Hz, 1H), 7.60 (dd, J=8.5, 7.7Hz, 2H), 7.56 (d, J=8.5 Hz, 2H), 7.48 (d, J=7.9 Hz, 1H), 7.36-7.30 (m,2H), 7.21 (ddd, J=12.2, 5.5, 1.6 Hz, 2H), 7.14 (s, 1H), 7.11 (d, J=8.5Hz, 2H), 3.26 (dd, J=13.8, 6.2 Hz, 2H), 1.85-1.72 (m, 3H), 1.66-1.42 (m,6H), 1.18-0.99 (m, 2H).

¹³C NMR (75 MHz, d₆-DMSO) δ 164.2, 153.6, 147.5, 141.6, 140.9, 134.8,134.1, 130.1, 127.2, 126.4, 126.0, 122.8, 119.9, 119.8, 117.8, 116.8,114.5, 114.2, 77.9, 35.5, 33.6, 30.3, 22.8

[M+H]⁺=412.3

Example 2: Compound (15) in Table I

According to procedure (D1), 2-pyridinamine (4.7 g, 50 mmoles, 1.1 eq.)was placed in a 3N NaOH aqueous solution (56 mL) and dichloromethane (24mL) was added to the solution. The reaction mixture was cooled down to0° C. with an ice bath and a solution of 4-nitrobenzoyl chloride (8.4 g,45 mmoles, 1 eq.) in dichloromethane (40 mL) was added dropwise. Thereaction mixture was then stirred at room temperature for 18 hours underan inert atmosphere of argon. The resulting precipitate was filtered andwashed with water and dichloromethane to afford4-nitro-N-(pyridin-2-yl)benzamide (6.7 g, 61%).

¹H NMR (300 MHz, d₆-DMSO) δ 10.91 (s, 1H), 8.80 (s, 1H), 8.52 (d, J=5.5Hz, 2H), 8.47 (d, J=7.9 Hz, 1H), 8.41 (d, J=7.9 Hz, 1H), 7.86 (t, J=7.9Hz, 1H), 7.79 (d, J=5.5 Hz, 2H).

According to procedure (C), 4-nitro-N-(pyridin-2-yl)benzamide (1.5 g,6.2 mmoles, 1 eq.) and tin (II) chloride dihydrate (7.0 g, 30.8 mmoles,5 eq.) were placed in EtOH (62 mL). The reaction mixture was heated at60° C. and stirred for 16 hours under an inert atmosphere of argon. Thereaction mixture was then concentrated under reduced pressure and theresulting residue was diluted with ethyl acetate. The organic phase waswashed with a 1N NaOH aqueous solution then with water, dried overMgSO₄, filtered and concentrated under reduced pressure to afford4-amino-N-(pyridin-2-yl)benzamide (273 mg, 21%).

¹H NMR (300 MHz, d₆-DMSO) δ 10.44 (s, 1H), 8.44 (d, J=6.3 Hz, 2H), 7.77(d, J=6.3 Hz, 2H), 7.18 (t, J=7.9 Hz, 1H), 7.12-7.03 (m, 2H), 6.78 (d,J=7.9 Hz, 1H), 5.38 (s, 2H).

2-Cyclopentylethan-1-amine hydrochloride (1.0 g, 7 mmoles, 1.1 eq.) wasplaced in a 3N NaOH aqueous solution (4.6 mL) and dichloromethane (1.1mL) was added to the solution. The reaction mixture was cooled down to0° C. with an ice bath and a solution of 3-bromobenzoyl chloride (0.8mL, 6 mmoles, 1 eq.) in dichloromethane (1.9 mL) was added dropwise. Thereaction mixture was then stirred at room temperature for 18 hours underan inert atmosphere of argon. Upon decantation, the organic phase waswashed with a saturated aqueous solution of brine, dried over MgSO₄,filtered and concentrated under reduced pressure to afford3-bromo-N-(2-cyclopentylethyl)benzamide (1.77 g, 98%).

¹H NMR (300 MHz, CDCl₃) δ 7.89 (t, J=1.7 Hz, 1H), 7.67 (d, J=7.9 Hz,1H), 7.62 (d, J=7.9 Hz, 1H), 7.30 (t, J=7.9 Hz, 1H), 6.07 (s, 1H), 3.46(dt, J=7.4, 5.9 Hz, 2H), 1.93-1.77 (m, 3H), 1.67-1.52 (m, 6H), 1.25-1.06(m, 2H).

According to procedure (A), a reaction mixture of3-bromo-N-(2-cyclopentylethyl)benzamide (296 mg, 1.0 mmole, 1 eq.),4-amino-N-(pyridin-2-yl)benzamide (213 mg, 1.0 mmole, 1 eq.), Pd₂(dba)₃(92 mg, 0.1 mmole, 10 mol %), XPhos (95 mg, 0.2 mmole, 20 mol %) andK₂CO₃ (553 mg, 4.0 mmoles, 4 eq.) in t-BuOH (4 mL) was heated in amicrowave reactor at 120° C. for 60 minutes. The reaction mixture wasthen concentrated under reduced pressure and the resulting residue wasdiluted with ethyl acetate. The organic phase was washed with water,dried over MgSO₄, filtered and concentrated under reduced pressure. Theresulting residue was purified by column chromatography on silica gel togiveN-(2-cyclopentylethyl)-3-((4-(pyridin-2-ylcarbamoyl)phenyl)amino)benzamide(15) (30 mg, 7%).

¹H NMR (300 MHz, d₆-DMSO) δ 10.46 (s, 1H), 8.83 (s, 1H), 8.44 (t, J=5.5Hz, 1H), 8.37 (d, J=3.8 Hz, 1H), 8.19 (d, J=8.4 Hz, 1H), 7.98 (d, J=8.7Hz, 2H), 7.87-7.77 (m, 1H), 7.65 (s, 1H), 7.45-7.36 (m, 2H), 7.30 (dt,J=6.5, 2.2 Hz, 1H), 7.15 (d, J=5.5 Hz, 1H), 7.11 (d, J=8.7 Hz, 2H), 3.26(dd, J=13.7, 6.4 Hz, 2H), 1.87-1.72 (m, 3H), 1.67-1.40 (m, 6H), 1.07 (m,2H).

¹³C NMR (75 MHz, d₆-DMSO) δ 164.2, 163.5, 150.8, 146.1, 145.3, 140.1,136.2, 134.3, 128.1, 127.5, 122.3, 119.3, 118.1, 117.6, 117.5, 115.7,112.8, 112.7, 35.7, 33.7, 30.5, 23.0 [M+H]⁺=429.1

Example 3: Compound (16) in Table I

According to procedure (D1), 2-pyridinamine (5.0 g, 53.1 mmoles, 1 eq.)was placed in a 3N NaOH aqueous solution (65.5 mL) and dichloromethane(5 mL) was added to the solution. The reaction mixture was cooled downto 0° C. with an ice bath and a solution of 4-nitrobenzoyl chloride (9.8g, 53.1 mmoles, 1 eq.) in dichloromethane (70 mL) was added dropwise.The reaction mixture was then stirred at room temperature for 18 hoursunder an inert atmosphere of argon. The resulting precipitate wasfiltered and washed with water and dichloromethane to afford4-nitro-N-(pyridin-2-yl)benzamide (5.8 g, 45%).

¹H NMR (300 MHz, d₆-DMSO) δ 11.16 (s, 1H), 8.40 (dd, J=4.8, 1.6 Hz, 1H),8.32 (d, J=8.9 Hz, 2H), 8.21 (d, J=9.0 Hz, 2H), 8.17 (d, J=8.4 Hz, 1H),7.90-7.82 (m, 1H), 7.23-7.15 (m, 1H).

According to procedure (C), 4-nitro-N-(pyridin-2-yl)benzamide (5.8 g,23.8 mmoles, 1 eq.) and tin (II) chloride dihydrate (27 g, 119 mmoles, 5eq.) were placed in EtOH (240 mL). The reaction mixture was heated at60° C. and stirred for 16 hours under an inert atmosphere of argon. Thereaction mixture was then concentrated under reduced pressure and theresulting residue was diluted with dichloromethane. The organic phasewas washed with a 1N NaOH aqueous solution then with a saturated aqueoussolution of brine, dried over MgSO₄, filtered and concentrated underreduced pressure to afford 4-amino-N-(pyridin-2-yl)benzamide (955 mg,19%).

¹H NMR (300 MHz, d₆-DMSO) δ 10.17 (s, 1H), 8.34 (d, J=3.8 Hz, 1H), 8.15(d, J=8.4 Hz, 1H), 7.80-7.75 (m, 3H), 7.09 (dd, J=6.4, 5.0 Hz, 1H), 6.57(d, J=8.6 Hz, 2H), 5.82 (br s, 2H).

2-Cyclohexylethan-1-amine (1.1 mL, 7.9 mmoles, 1.1 eq.) was placed in a3N NaOH aqueous solution (5.3 mL) and dichloromethane (1 mL) was addedto the solution. The reaction mixture was cooled down to 0° C. with anice bath and a solution of 3-bromobenzoyl chloride (945 μL, 7.1 mmoles,1 eq.) in dichloromethane (2.5 mL) was added dropwise. The reactionmixture was then stirred at room temperature for 18 hours under an inertatmosphere of argon. Upon decantation, the organic phase was washed witha saturated aqueous solution of brine, dried over MgSO₄, filtered andconcentrated under reduced pressure to afford3-bromo-N-(2-cyclohexylethyl)benzamide (2.0 g, 90%).

¹H NMR (300 MHz, CDCl₃) δ 7.89 (t, J=1.7 Hz, 1H), 7.67 (d, J=7.8 Hz,1H), 7.62 (d, J=7.8 Hz, 1H), 7.31 (t, J=7.9 Hz, 1H), 6.00 (bs, 1H), 3.47(dt, J=7.5, 5.8 Hz, 2H), 1.81-1.62 (m, 4H), 1.51 (dd, J=14.6, 7.1 Hz,2H), 1.31-1.12 (m, 5H), 1.04-0.85 (m, 2H).

According to procedure (A), a reaction mixture of3-bromo-N-(2-cyclohexylethyl)benzamide (310 mg, 1.0 mmole, 1 eq.),4-amino-N-(pyridin-2-yl)benzamide (213 mg, 1.0 mmole, 1 eq.), Pd₂(dba)₃(92 mg, 0.1 mmole, 10 mol %), XPhos (95 mg, 0.2 mmole, 20 mol %) andK₂CO₃ (553 mg, 4.0 mmoles, 4 eq.) in t-BuOH (4 mL) was heated in amicrowave reactor at 120° C. for 60 minutes. The reaction mixture wasthen concentrated under reduced pressure and the resulting residue wasdiluted with ethyl acetate. The organic phase was washed with asaturated aqueous solution of brine, dried over MgSO₄, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby column chromatography on silica gel and then triturated with diethylether to giveN-(2-cyclohexylethyl)-3-((4-(pyridin-2-ylcarbamoyl)phenyl)amino)benzamide(16) (78 mg, 18%).

¹H NMR (300 MHz, d₆-DMSO) δ 10.46 (s, 1H), 8.83 (s, 1H), 8.42-8.37 (m,2H), 8.19 (d, J=8.4 Hz, 1H), 7.98 (d, J=8.7 Hz, 2H), 7.82 (t, J=8.8 Hz,1H), 7.64 (s, 1H), 7.42-7.35 (m, 2H), 7.32-7.29 (m 1H), 7.17-7.13 (m,1H), 7.10 (d, J=8.6 Hz, 2H), 3.28 (dd, J=13.3, 6.8 Hz, 2H), 1.78-1.57(m, 5H), 1.43 (dd, J=14.2, 6.9 Hz, 2H), 1.34-1.12 (m, 4H), 0.99-0.82 (m,2H).

¹³C NMR (75 MHz, d₆-DMSO) δ 166.4, 165.7, 152.9, 148.3, 147.5, 142.3,138.4, 136.5, 130.2, 129.7, 124.5, 121.5, 120.3, 119.8, 117.9, 115.0,114.9, 37.5, 37.1, 35.3, 33.2, 26.5, 26.2

[M+H]⁺=429.1

Example 4: Compound (115) in Table I

According to procedure (J), a solution of methyl 4-amino-3-bromobenzoate(3.00 g, 12.8 mmoles, 1 eq.) and potassium cyclopropyltrifluoroborate(2.84 g, 19.2 mmoles, 1.5 eq.) in toluene (52.5 mL) and water (13.5 mL)was degassed with argon during 5 minutes then tripotassium phosphate(6.88 g, 31.9 mmoles, 2.5 eq.), RuPhos (239 mg, 511 μmoles, 0.04 eq.)and palladium(II) acetate (57.9 mg, 256 μmoles, 0.02 eq.) were added.The reaction mixture was heated at 110° C. and stirred for 2 h30 underinert atmosphere. Upon cooling down to room temperature, it was filteredover a pad of celite and the pad was washed with EtOAc. A saturatedaqueous solution of brine was then added to the filtrate and the mixturewas extracted with EtOAc. The combined organic layers were dried overMgSO₄, filtered and concentrated under reduced pressure. The resultingresidue was purified by column chromatography on silica gel to givemethyl 4-amino-3-cyclopropylbenzoate (2.02 g, 81%).

¹H NMR (400 MHz, d₆-DMSO) δ 7.53 (dd, J=8.4, 2.0 Hz, 1H), 7.42 (d, J=1.9Hz, 1H), 6.63 (d, J=8.4 Hz, 1H), 5.87 (s, 2H), 3.73 (s, 3H), 1.65 (tt,J=8.3, 5.4 Hz, 1H), 0.95-0.82 (m, 2H), 0.54-0.40 (m, 2H).

3-Bromophenol (701 mg, 3.97 mmoles, 1.2 eq.) was placed inN,N-dimethylformamide (4 mL) with Cs₂CO₃ (1.30 g, 3.97 mmoles, 1.2 eq.).Upon addition of (3-bromopropyl)cyclohexane (715 mg, 3.31 mmoles, 1.0eq.), the reaction mixture was stirred for 16 hours under an inertatmosphere of argon. The reaction mixture was partitioned between ethylacetate and a saturated aqueous solution of NaHCO₃. Upon extraction withethyl acetate, the combined organic layers were dried over MgSO₄,filtered and concentrated under reduced pressure. The resulting residuewas purified by column chromatography on silica gel to give1-bromo-3-(3-cyclohexylpropoxy)benzene (882 mg, 90%).

¹H NMR (500 MHz, d₆-DMSO) δ 7.22 (t, J=8.1 Hz, 1H), 7.14-7.08 (m, 2H),6.93 (dd, J=8.3, 2.3 Hz, 1H), 3.95 (t, J=6.5 Hz, 2H), 1.68 (tt, J=15.1,9.2 Hz, 7H), 1.32-1.06 (m, 6H), 0.92-0.82 (m, 2H).

According to procedure (A), a reaction mixture of1-bromo-3-(3-cyclohexylpropoxy)benzene (547 mg, 1.84 mmole, 1.1 eq.),methyl 4-amino-3-cyclopropyl-benzoate (320 mg, 1.67 mmol, 1 eq.),BrettPhos Pd G3 (31.9 mg, 33.5 μmol, 0.02 eq) and Cs₂CO₃ (818 mg, 2.51mmol, 1.5 eq.) in anhydrous DMF (8 mL) was degassed with argon andheated at 80° C. for 75 minutes under inert atmosphere. The reactionmixture was then cooled down to room temperature, filtered over a pad ofcelite and the pad was washed with EtOAc. Brine was then added to thefiltrate and the mixture was extracted with EtOAc. The combined organiclayers were dried over MgSO₄, filtered and concentrated under reducedpressure. The resulting residue was purified by column chromatography onsilica gel to give methyl4-{[3-(3-cyclohexylpropoxy)phenyl]amino}-3-cyclopropylbenzoate (1.35 g,80%).

¹H NMR (400 MHz, d₆-DMSO) δ 7.82 (s, 1H), 7.66 (dd, J=8.5, 2.0 Hz, 1H),7.54 (d, J=2.0 Hz, 1H), 7.24-7.14 (m, 2H), 6.76 (d, J=7.9 Hz, 1H), 6.73(t, J=2.1 Hz, 1H), 6.56 (dd, J=8.1, 2.2 Hz, 1H), 3.92 (t, J=6.5 Hz, 2H),3.78 (s, 3H), 1.94 (ddd, J=13.8, 8.3, 5.4 Hz, 1H), 1.75-1.58 (m, 7H),1.35-1.08 (m, 6H), 1.04-0.94 (m, 2H), 0.88 (q, J=10.0, 9.3 Hz, 2H),0.65-0.56 (m, 2H).

According to procedure (E), methyl4-{[3-(3-cyclohexylpropoxy)phenyl]amino}-3-cyclopropylbenzoate (575 mg,1.34 mmole, 1 eq.) was placed in methanol (10 mL) and an aqueoussolution of 2M NaOH (4.7 mL, 9.4 mmoles, 7 eq.) was added. The reactionmixture was heated at 80° C. and stirred for 3 hours. It was thenconcentrated under reduced pressure and, after addition of an aqueoussolution of 2M HCl (7.0 mL, 14 mmoles, 10.5 eq), extracted withdichloromethane. The combined organic phases were dried over magnesiumsulphate, filtered and concentrated under reduced pressure to give4-{[3-(3-cyclohexylpropoxy)phenyl]amino}-3-cyclopropylbenzoic acid (540mg, 97%).

¹H NMR (400 MHz, d₆-DMSO) δ 12.37 (s, 1H), 7.76 (s, 1H), 7.64 (dd,J=8.5, 2.0 Hz, 1H), 7.52 (d, J=1.9 Hz, 1H), 7.18 (t, J=8.6 Hz, 2H), 6.74(d, J=7.9 Hz, 1H), 6.71 (d, J=2.1 Hz, 1H), 6.53 (dd, J=8.1, 2.1 Hz, 1H),3.91 (t, J=6.5 Hz, 2H), 1.94 (ddd, J=13.6, 8.4, 5.4 Hz, 1H), 1.75-1.58(m, 7H), 1.35-1.09 (m, 6H), 0.98 (dd, J=4.0, 2.0 Hz, 2H), 0.88 (q,J=10.1, 9.3 Hz, 2H), 0.65-0.56 (m, 2H).

According to procedure (F),4-{[3-(3-cyclohexylpropoxy)phenyl]amino}-3-cyclopropylbenzoic acid (50.0mg, 127 μmoles, 1 eq.) and aniline (12.2 μL, 133 μmoles, 1.05 eq.) wereplaced in anhydrous N,N-dimethylformamide (650 μL). HATU (48.3 mg, 127μmoles, 1 eq.) and DIPEA (44.4 μL, 254 μmoles, 2 eq.) were added and theresulting reaction mixture was stirred at room temperature for 16 hours.The reaction was quenched with 1M aqueous hydrochloric acid andextracted with ethyl acetate. The combined organic phases were driedover magnesium sulphate, filtered and concentrated under reducedpressure. The resulting residue was purified by column chromatography onsilica gel to give4-{[3-(3-cyclohexylpropoxy)phenyl]amino}-3-cyclopropyl-N-phenylbenzamide(115) (42.0 mg, 67%).

¹H NMR (400 MHz, d₆-DMSO) δ 9.96 (s, 1H), 7.78-7.67 (m, 4H), 7.57 (d,J=2.0 Hz, 1H), 7.33 (t, J=7.9 Hz, 2H), 7.23 (d, J=8.5 Hz, 1H), 7.16 (t,J=8.1 Hz, 1H), 7.07 (t, J=7.4 Hz, 1H), 6.74-6.68 (m, 1H), 6.67 (t, J=2.1Hz, 1H), 6.48 (dd, J=8.1, 2.1 Hz, 1H), 3.91 (t, J=6.5 Hz, 2H), 2.04-1.92(m, 1H), 1.75-1.57 (m, 7H), 1.35-1.09 (m, 6H), 1.04-0.95 (m, 2H), 0.88(q, J=10.1, 9.5 Hz, 2H), 0.76-0.67 (m, 2H).

¹³C NMR (151 MHz, d₆-DMSO) δ 165.6, 160.0, 146.2, 144.9, 139.9, 131.8,130.2, 128.9, 126.8, 126.7, 126.4, 123.7, 120.9, 116.2, 111.4, 107.5,105.3, 68.0, 37.2, 33.7, 33.3, 26.6, 26.6, 26.3, 11.6, 7.8

[M+H]⁺=469.2

Example 5: Compound (35) in Table I

According to procedure (F), benzene-1,4-diamine (4.0 g, 37 mmoles, 3.0eq.) was placed in tetrahydrofurane (37 mL) and N,N-dimethylformamide(12 mL). A 2.2M K₂CO₃ aqueous solution (6.8 mL, 13.6 mmoles, 1.1 eq.)was added to the solution and Boc₂O (2.6 mL, 12.3 mmoles, 1.0 eq.) wasthen added dropwise. The reaction mixture was stirred at roomtemperature for 64 hours. The reaction mixture was then concentratedunder reduced pressure and the resulting residue was diluted with ethylacetate. The organic phase was washed with water, dried over MgSO₄,filtered and concentrated under reduced pressure. The resulting residuewas purified by column chromatography on silica gel to give tert-butyl(4-aminophenyl)carbamate (1.6 g, 62%).

¹H NMR (300 MHz, CDCl₃) δ 7.13 (d, J=8.5 Hz, 2H), 6.63 (d, J=8.5 Hz,2H), 6.32 (s, 1H), 3.54 (s, 2H), 1.50 (s, 9H).

According to procedure (G), a reaction mixture of tert-butyl(4-aminophenyl)carbamate (1.6 g, 7.7 mmoles, 1.0 eq.),2-pyridinecarboxylic acid (1.0 g, 8.5 mmoles, 1.1 eq.), EDCI·HCl (1.6 g,8.5 mmoles, 1.1 eq.), N,N-diisopropylethylamine (3.8 mL, 23 mmoles, 3.0eq.) and HOBt (1.1 g, 8.5 mmoles, 1.1 eq.) in anhydrous dichloromethane(15 mL) was stirred at room temperature for 24 hours under an inertatmosphere of argon. The organic phase was washed with water, dried overMgSO₄, filtered and concentrated under reduced pressure. The resultingresidue was purified by column chromatography on silica gel to givetert-butyl N-[4-(pyridine-2-amido)phenyl]carbamate (983 mg, 41%).

¹H NMR (300 MHz, CDCl₃) δ 9.98 (s, 1H), 8.61 (d, J=4.5 Hz, 1H), 8.29 (d,J=7.7 Hz, 1H), 7.91 (td, J=7.7, 1.5 Hz, 1H), 7.72 (d, J=8.8 Hz, 2H),7.48 (ddd, J=7.7, 4.5, 1.5 Hz, 1H), 7.40 (d, J=8.8 Hz, 2H), 6.61 (s,1H), 1.52 (s, 9H).

According to procedure (H), tert-butylN-[4-(pyridine-2-amido)phenyl]carbamate (983 mg, 3.1 mmoles, 1 eq.) wasplaced in dichloromethane (6.3 mL) and trifluoroacetic acid (5.1 mL,68.2 mmoles, 22 eq.) was added to the solution. The reaction mixture wasstirred at room temperature for 1 hour and then cooled down to 0° C.with an ice bath. Water and then K₂CO₃ were added until reaching pH>7.The aqueous phase was extracted with dichloromethane. The organic phaseswere gathered, dried over MgSO₄, filtered and concentrated under reducedpressure to give N-(4-aminophenyl)pyridine-2-carboxamide (659 mg, 99%).

¹H NMR (300 MHz, CDCl₃) δ 9.85 (s, 1H), 8.60 (d, J=4.5 Hz, 1H), 8.29 (d,J=7.7 Hz, 1H), 7.89 (td, J=7.7, 1.5 Hz, 1H), 7.57 (d, J=8.7 Hz, 2H),7.46 (ddd, J=7.7, 4.5, 1.5 Hz, 1H), 6.72 (d, J=8.7 Hz, 2H), 3.63 (s,2H).

2-Cyclopentylethan-1-amine hydrochloride (1.0 g, 7 mmoles, 1.1 eq.) wasplaced in a 3N NaOH aqueous solution (4.6 mL) and dichloromethane (1.1mL) was added to the solution. The reaction mixture was cooled down to0° C. with an ice bath and a solution of 3-bromobenzoyl chloride (0.8mL, 6 mmoles, 1 eq.) in dichloromethane (1.9 mL) was added dropwise. Thereaction mixture was then stirred at room temperature for 18 hours underan inert atmosphere of argon. Upon decantation, the organic phase waswashed with a saturated aqueous solution of brine, dried over MgSO₄,filtered and concentrated under reduced pressure to afford3-bromo-N-(2-cyclopentylethyl)benzamide (1.77 g, 98%).

¹H NMR (300 MHz, CDCl₃) δ 7.89 (t, J=1.7 Hz, 1H), 7.67 (d, J=7.9 Hz,1H), 7.62 (d, J=7.9 Hz, 1H), 7.30 (t, J=7.9 Hz, 1H), 6.07 (s, 1H), 3.46(dt, J=7.4, 5.9 Hz, 2H), 1.93-1.77 (m, 3H), 1.67-1.52 (m, 6H), 1.25-1.06(m, 2H).

According to procedure (A), a reaction mixture of3-bromo-N-(2-cyclopentylethyl)benzamide (296 mg, 1.0 mmole, 1 eq.),N-(4-aminophenyl)pyridine-2-carboxamide (213 mg, 1.0 mmole, 1 eq.),Pd₂(dba)₃ (92 mg, 0.1 mmole, 10 mol %), XPhos (95 mg, 0.2 mmole, 20 mol%) and K₂CO₃ (553 mg, 4.0 mmoles, 4 eq.) in t-BuOH (4 mL) was heated ina microwave reactor at 120° C. for 60 minutes. The reaction mixture wasthen concentrated under reduced pressure and the resulting residue wasdiluted with ethyl acetate. The organic phase was washed with water,dried over MgSO₄, filtered and concentrated under reduced pressure. Theresulting residue was purified by column chromatography on silica gel togiveN-(4-((3-((2-cyclopentylethyl)carbamoyl)phenyl)amino)phenyl)picolinamide(35) (89 mg, 21%), upon recrystallisation.

¹H NMR (300 MHz, d₆-DMSO) δ 10.54 (s, 1H), 8.74 (d, J=4.4 Hz, 1H), 8.36(t, J=5.4 Hz, 1H), 8.29 (s, 1H), 8.16 (d, J=7.7 Hz, 1H), 8.07 (td,J=7.7, 1.5 Hz, 1H), 7.82 (d, J=8.8 Hz, 2H), 7.71-7.62 (m, 1H), 7.51 (s,1H), 7.34-7.20 (m, 2H), 7.16-7.10 (m, 3H), 3.25 (dd, J=13.4, 6.5 Hz,2H), 1.82-1.72 (m, 3H), 1.68-1.45 (m, 6H), 1.12-1.08 (m, 2H).

¹³C NMR (75 MHz, d₆-DMSO) δ 164.9, 160.5, 148.7, 146.9, 142.6, 137.6,136.6, 134.5, 130.0, 127.6, 125.3, 120.8, 120.0, 116.7, 116.4, 116.1,113.1, 35.9, 34.0, 30.7, 23.2

[M+H]⁺=429.1

Pharmacological Data Example 6: Chikungunya Virus

The compounds of the invention have been the subject of pharmacologicaltests which have demonstrated their relevance as active substances intherapy and in particular for preventing, inhibiting or treatingChikungunya virus infection.

Material and Methods

Inhibition of Chikungunya Virus (CHIKV) Production in Infected HEK293TCell Line.

The ability of the compounds to inhibit viral replication was assessedwith an experiment in which infected cells were treated by compounds offormula (I) at 1 μM. As a positive control for inhibition ofChikungunya, Ribavirin was used. Toxicity of the compounds was assessedin parallel.

Amplification of Cells

Human embryonic kidney cells 293T (HEK293T, CRL-11268) were maintainedin Dulbecco's modified Eagle's Medium (DMEM, 31966-021, Thermo FisherScientific) supplemented with 10% of fetal bovine serum (FBS),penicillin and streptomycin. After removal of the medium, cells werewashed with Ca²⁺ and Mg²⁺-free salt solution to remove all traces ofserum. After aspiration of wash solution, cells were dissociated with0.25% Trypsin-EDTA solution and incubated 30 s at least in 37° C.incubator. Concentration of cell suspension was determined by anautomatic cell counter (EVE, NanoEntek) and, if needed, adjusted to0.33×10⁶ cells/mL with DMEM medium supplemented with 10% FBS.

Preparation of the Compounds

100 μL of the cell suspension were dispatched in a ViewPlate-96 Black(6005182, PerkinElmer) and in a transparent 96-well cell culture plate(655180, Greiner bio-one). After an incubation for 24 h at 37° C. under5% of CO₂, compounds were added at the proper concentration.

Screen at 1 μM

An intermediate dilution was prepared with DMSO (D8418, Sigma) at 2 mMin a 96-well V-bottom microplate from the stock solution:

Mix 1 μL of the 50 mM stock library in 25 μL of DMSO.

Mix 2 μL of the 25 mM stock library in 25 μL of DMSO.

Determination of IC₅₀ Values

An intermediate dilution was prepared with DMSO (D8418, Sigma) at 25 mMin a 96-well V-bottom microplate from the stock solution:

Mix 2 μL of the 50 mM stock library in 2 μL of DMSO.

Perform serial dilution in 2 μL of DMSO 13 times to reach 0.0015 mM.Proceed as follows in table III:

TABLE III Volume of Concentration DMSO 100% (mM) (μL) Volume of solutionA 12.5 2 2 μL of 50 mM solution B 6.25 2 2 μL of solution A C 3.125 2 2μL of solution B D 1.56 2 2 μL of solution C E 0.78 2 2 μL of solution DF 0.39 2 2 μL of solution E G 0.195 2 2 μL of solution F H 0.0976 2 2 μLof solution G I 0.0488 2 2 μL of solution H J 0.0244 2 2 μL of solutionI K 0.0122 2 2 μL of solution J L 0.0061 2 2 μL of solution K M 0.0030 22 μL of solution L N 0.0015 2 2 μL of solution M

For both screen and determination of IC₅₀, 1 μL of each solution wasadded in a 1 mL Masterblock 96 wells (Greiner bio-one, 780261)containing 1 mL of DMEM medium. As a positive control, 5 μL of a 80 mMRibavirin solution (R9644, Sigma) is added to 1 mL of DMEM. On the otherhand, DMSO is used as a negative control.

Infection

Cells were infected with 30 μL of CHIKV strain of La Réunion outbreak(LR2006-OPY1) with GFP modification in 5′ (CHIK 5′LR) (Tsetsarkin K,Higgs S, McGee C E, De Lamballerie X, Charrel R N, Vanlandingham D L.Infectious Clones of Chikungunya Virus (La Réunion Isolate—Ref-SKU:001N-EVA249 (PMID: 17187566) available at the following address:https://www.european-virus-archive.com/nucleic-acid/chikv-lr-5gfp-infectious-clone)for Vector Competence Studies. Vector Borne Zoonotic Dis. 2006; 6(4)).This modified virus was used to infect cells at MOI 0.1. The LR2006-OPY1strain of CHIKV (CHIKV-LR) was obtained from the World Reference Centerfor Arboviruses at the University of Texas Medical Branch, Galveston,Tex. This strain was originally isolated from the serum of a febrileFrench patient returning from La Réunion Island.

Cell Lysis

Medium was removed after 22 h at 37° C. under 5% of CO₂ and cells werewashed as described above. 60 μL of RIPA buffer (50 mM Tris-HCl pH8, 100mM NaCl, 1 mM MgCl₂, 1% Triton X-100) was added to cells and incubatedfor at least 20 min before reading fluorescence signal. Pierce 660 nmProtein Assay Reagent (22660, Thermo scientific) was used to normalizefluorescence signal by protein quantity.

CellTiter 96® AQueous One Solution Cell Proliferation Assay (MTS)(G3581, Promega) was used to check the toxicity of the compounds. Weadded 20 μL of MTS solution and read absorbance at 492 nm one hourlater.

Results

-   -   A first round of experiments has been performed wherein the        results are expressed as inhibition percentage, which is        calculated as follows, through the following steps:

1. Fluorescence intensity (FI)/Absorbance 660 nm (A660)=A

This ratio allows considering the infection (GFP virus) to the proteinamount.

2. A′=A—background noise of non-infected plate,

3. B=Fluorescence intensity (FI)/Absorbance 660 nm (A660) of infectedbut non treated plates,

4. C=A′/B, which is then converted as the percentage of infection aftertreatment, compared to non-treated sample, and subsequently as theinfection percentage. For instance, a value of 100 in Table IV herebelow means that, after treatment, the signal attributed to GFPfluorescence is abolished, which is correlated to the absence ofinfection.

5. C′=100−C

This value corresponds to the inhibition's percentage.

The following Table IV encompasses said C′ value for some compounds, ascalculated above with a mean of 2 experiments, and correspondingstandard deviation.

Some values were originally above 100. In these cases, the value hasbeen lowered to 100. This means that some molecules also have an impacton the viability of the cells. In other words, the A value may be lowerthan the background noise.

Moreover, for each measure, the test was performed with Ribavirin ascontrol. The value of the inhibition percentage was checked, giving100%.

TABLE IV % CHIKV Inhibition Ex Mean (n = 2) Standard deviation (n = 2) 198 3 2 74 28 4 99 2 6 98 3 9 98 2 14 93 7 15 98 1 16 100 0 32 99 2 35100 0

-   -   A second round of experiments has been performed, giving the        results as IC₅₀ values.

The IC₅₀ values range between 0.1 nM and 1 μM, in particular between 0.5and 500 nM and even more particularly between 1 and 400 nM, for examplebetween 1 and 200 nM and particularly for compounds 6, 14, 15, 16, 32and 35 for which the IC₅₀ values range between 200 and 500 nM. Forexample, compounds 12 and 13 have an IC₅₀ value ranging between 1 and200 nM.

Conclusion

Based on the previous results, it can be concluded that the compounds offormula (I) are suitable chemical compounds for treating and/orpreventing RNA virus infections caused by RNA viruses of group IV, moreparticularly, alphavirus infections, and most particularly Chikungunyavirus infections.

Example 7: RSV Virus

The compounds of the invention have been the subject of pharmacologicaltests which have demonstrated their relevance as active substances intherapy and in particular for preventing, inhibiting or treating RSVvirus infection.

Material and Methods

Protocol for Screening Antiviral Compounds for RSV Inhibition andCytotoxicity Using Viral ToxGlo Assay

HEp-2 cells were maintained in Eagle's minimum essential medium (EMEM)with Earle's BSS adjusted to contain 2 mM L-glutamine, 10% fetal bovineserum, 100 U/ml penicillin and 100 μg/ml streptomycin. For the purposesof the screening assay they were grown to 90% confluency, trypsinizedand recovered. The trypsin was neutralised with cell culture media andcells were centrifuged at 150×g for 5 minutes before discarding thesupernatant and resuspending cell pellet in assay media (EMEM withEarle's BSS adjusted to contain 2 mM L-glutamine, 2% fetal bovine serumand 100 U/ml penicillin and 100 μg/ml streptomycin). The cells wereseeded into white clear-bottomed cell culture plates at a density of1.5×10⁴ cells/well in 50 μl and 4×10³ cells/well in 25 μl for 96 wellplates and 384 well plates respectively. For the media/backgroundcontrol column assay media only was added. Cell plates were placed in ahumid chamber and incubated overnight at 37° C./5% CO₂. After overnightincubation cells were checked for confluency and healthy appearance.

Test articles were made up at 10× test concentration in a maximum DMSOconcentration of 10% (final assay concentration maximal 1% DMSO) andadded to the cell plates in volumes of 10 μl for 96 well plates and 5 μlfor 384 well plates. For cell control and virus control wells the testarticle solvent only was added. Virus or assay media for cytotoxicitytest wells and media/cell control wells was added immediately after testarticles at an MOI of 0.5, 40 or 20 μl for 96 and 384 well platesrespectively. Virus suspension was prepared by thawing RSV A2 frozenstocks and diluting to the required concentration of plaque formingunits in assay media on ice.

Cell plates were further incubated inside a humid chamber for 72 h p.iat 37° C./5% CO₂. After the incubation period cells were observed underthe microscope to check for characteristic cytopathic effect in viruscontrol wells and healthy cells in the cell control wells. After plateswere adjusted to room temperature 20/40 μl Viral ToxGlo (Promega) wasadded to each well of the 384/96 well cell plates. Plates were incubatedat room temperature, protected from light on a plate rocker for 20minutes before measuring the luminescence on a spectrophotometer (BiotekSynergy HTX).

RSV inhibition was calculated as percentage of cytopathic effectinhibition relative to the virus control and cytotoxicity as percentageof cell survival relative to cell control wells. This allowed EC₅₀values to be calculated for each test article where a virus inhibitionor cytotoxic dose response was identified. EC₅₀ values ranging between0.001 μM and 2.5 μM were found, and more particularly for compound 12,13, 16 and 115.

TABLE V Ex EC₅₀ (nM) 12 370 < EC₅₀ < 2500 13 370 < EC₅₀ < 2500 16 1168115 229

Conclusion

Based on the previous results, it can be concluded that the compounds offormula (I) are suitable chemical compounds for treating and/orpreventing RNA virus infections caused by RNA viruses of group V, moreparticularly, pneumovirus infections, and most particularly RSV virusinfections.

Example 8: Dengue 2 Virus

The compounds of the invention have been the subject of pharmacologicaltests which have demonstrated their relevance as active substances intherapy and in particular for preventing, inhibiting or treating Dengue2 virus infection.

Material and Methods

Protocol for Screening Antiviral Compounds for DENV-2 Inhibition andCytotoxicity Using Viral ToxGlo Assay

A549 cells were maintained in Dulbecco's Modified Eagle Medium (DMEM)supplemented with 10% fetal bovine serum, 100 U/ml penicillin and 100μg/ml streptomycin. For the purposes of the screening assay they weregrown to 90% confluency, trypsinized and recovered. The trypsin wasneutralised with cell culture media and cells were centrifuged at 150×gfor 5 minutes before discarding the supernatant and resuspending cellpellet in assay media (DMEM supplemented with 2% fetal bovine serum and100 U/ml penicillin and 100 μg/ml streptomycin). The cells were seededinto 96-well white clear-bottomed cell culture plates at a density of1.0×104 cells/well in 50 μl. For the media/background control columnassay media only was added. Cell plates were placed in a humid chamberand incubated overnight at 37° C./5% CO₂. After overnight incubationcells were checked for confluency and healthy appearance.

Test compounds were prepared at a final concentration of 10 μM in amaximum DMSO concentration of 1% (final assay concentration maximal 0.1%DMSO) and added to the cell plates in volumes of 10 μl. For cell controland virus control wells the test article solvent only was added. As apositive inhibition control, 7-Deaza-2′-C-methyladenosine was added at100 μM in 3 wells. Virus (DENV-2 strain 16681) or assay media forcytotoxicity test wells and media/cell control wells was addedimmediately after test articles at an MOI of 0.5, 40 for 96 well platesrespectively. Virus suspension was prepared by thawing DENV-2 frozenstocks and diluting to the required concentration of plaque formingunits in assay media.

Cell plates were further incubated inside a humid chamber for 5 days p.iat 37° C./5% CO2. After the incubation period cells were observed underthe microscope to check for characteristic cytopathic effect in viruscontrol wells and healthy cells in the cell control wells. After plateswere adjusted to room temperature 20 μl Viral ToxGlo (Promega) was addedto each well of the 96-well cell plates. Plates were incubated at roomtemperature for 5 minutes before measuring the luminescence on aspectrophotometer (Envision, PerkinElmer).

DENV-2 inhibition was calculated as percentage of cytopathic effectinhibition relative to the virus control and cytotoxicity as percentageof cell survival relative to cell control wells.

TABLE VI % DENV-2 Inhibition Ex Mean (n = 3) 12 96 13 86 15 107 35 66

Conclusion

Based on the previous results, it can be concluded that the compounds offormula (I) are suitable chemical compounds for treating and/orpreventing RNA virus infections caused by RNA viruses of group IV, moreparticularly, flavivirus infections, and most particularly Dengue 2virus infections.

The present invention further relates to a pharmaceutical compositioncomprising at least one new compound as defined above or any of itspharmaceutically acceptable salts, or at least any of compounds (3) to(18), (32) to (35), (91) to (125) as defined above or any of itspharmaceutically acceptable salts and also at least one pharmaceuticallyacceptable excipient.

Pharmaceutical compositions of the invention can contain one or morecompound(s) of the invention in any form described herein.

Still a further object of the present invention consists of the use ofat least one compound of formula (I), as defined above, and compounds(1) to (18) and (32) to (35) and (91) to (122) as defined above, or oneof their pharmaceutically acceptable salts according to the presentinvention for preparing a drug to prevent or treat, in a subject, a RNAvirus infection caused by a RNA virus from group IV or Group V accordingto the Baltimore classification, and for example a Chikungunyainfection, a Dengue infection, an Influenza infection or a RSVinfection.

Therefore, the present invention relates to one compound of formula (I),as defined above, and compounds (1) to (18) and (32) to (35) and (91) to(122) or one of their acceptable salts as an agent for inhibiting,preventing or treating a RNA virus infection, and most preferably a RNAvirus infection from group IV or V, and for example a Chikungunyainfection, a Dengue infection, an Influenza infection or a RSVinfection.

According to a particular embodiment, the treatment is continuous ornon-continuous.

A “continuous treatment” means a long-term treatment which can beimplemented with various administration frequencies, such as once everyday, every three days, once a week, or once every two weeks or onceevery month.

According to one embodiment, the compound of formula (I), or anyone ofits pharmaceutically acceptable salts, is administered at a dose varyingfrom 0.1 to 1000 mg, in particular varying from 0.1 to 10 mg, or forexample varying from 10 to 200 mg, or for example varying from 200 to1000 mg.

Another object of the invention relates to a therapeutic method fortreating and/or preventing a subject from a RNA virus infection, andmost preferably a RNA virus infection caused by a virus belonging togroup IV or V of the Baltimore classification comprising theadministration of a therapeutically effective quantity of a compound offormula (I), compounds (1) to (18) and (32) to (35) and (91) to (122),as defined above, or one of their acceptable salts.

In a specific embodiment, the invention provides a use of a compound offormula (I) according to the invention or a pharmaceutically acceptablesalt thereof or a pharmaceutically active derivative thereof or a methodaccording to the invention wherein the compound of formula (I) is to beadministered in combination with a co-agent useful in the treatment ofsaid RNA virus infection, and most preferably said RNA virus infectionfrom group IV or V, and for example Chikungunya infection, Dengueinfection, Influenza infection or RSV infection.

The compounds can be administered through any mode of administrationsuch as, for example, intramuscular, intravenous, intranasal or oralroute, etc.

Compounds of the present invention may, in appropriate cases, beadministered as prodrugs, such as esters, of compounds with which theinvention is concerned. “Prodrug” means a compound which is convertiblein vivo by metabolic means (e.g. by hydrolysis, reduction or oxidation)to a compound of the present invention. For example, an ester prodrug ofa compound of the present invention may be convertible by hydrolysis invivo to the parent molecule. Suitable esters of compounds of the presentinvention are for example acetates, citrates, lactates, tartrates,malonates, oxalates, salicylates, propionates, succinates, fumarates,maleates, methylene-bis-β-hydroxynaphthoates, gentisates, isethionates,di-p-toluoyltartrates, methanesulphonates, ethanesulphonates,benzenesulphonates, p-toluenesulphonates, cyclohexylsulfamates andquinates. Examples of ester prodrugs are those described by F. J.Leinweber, Drug Metab. Res., 1987, 18, 379. As used herein, referencesto the compounds of the present invention are meant to also include anyprodrug or metabolite forms.

The inventive composition can further include one or more additives suchas diluents, excipients, stabilizers and preservatives. Such additivesare well known to those skilled in the art and are described notably in“Ullmann's Encyclopedia of Industrial Chemistry, 6^(th) Ed.” (variouseditors, 1989-1998, Marcel Dekker) and in “Pharmaceutical Dosage Formsand Drug Delivery Systems” (ANSEL et al., 1994, WILLIAMS & WILKINS).

The aforementioned excipients are selected according to the dosage formand the desired mode of administration.

According to another embodiment, pharmaceutically acceptablecompositions of this invention can be administered to humans and otheranimals orally, rectally, parenterally, intracisternally,intravaginally, intraperitoneally, topically (as by powders, ointments,or drops), bucally, as an oral or nasal spray, or the like, depending onthe severity of the infection being treated.

Compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention may be aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium.

Compositions of this invention may be administered in any manner,including, but not limited to, orally, parenterally, sublingually,transdermally, vaginally, rectally, transmucosally, topically,intranasally via inhalation, via buccal or intranasal administration, orcombinations thereof. Parenteral administration includes, but is notlimited to, intravenous, intra-arterial, intra-peritoneal, subcutaneous,intramuscular, intra-thecal, and intra-articular. The compositions ofthis invention may also be administered in the form of an implant, whichallows slow release of the compositions as well as a slow controlledi.v. infusion.

For example, a compound of formula (I) can be present in anypharmaceutical form which is suitable for enteral or parenteraladministration, in association with appropriate excipients, for examplein the form of plain or coated tablets, hard gelatine, soft shellcapsules and other capsules, suppositories, or drinkable, such assuspensions, syrups, or injectable solutions or suspensions, in doseswhich enable the daily administration of from 0.1 to 1000 mg of activesubstance.

In a particular embodiment, a compound of formula (I) according to theinvention is administered orally.

Oral route of administration is in particular preferred in theprophylaxis or treatment aspect of the invention.

The invention claimed is:
 1. A method for treating a subject for a RNAvirus infection caused by a virus belonging to group IV or V of theBaltimore classification comprising administering to a patient in needthereof of a therapeutically effective quantity of a compound of formula(I):

wherein:

ring and

ring independently mean a phenylene or a pyridylene group, X¹ representsan alkenylene group, a —NH—CO— group, a —CO—NH— group, Y¹ represents anaryl group selected from a pyridyl group, a pyrazinyl group or apyrimidinyl group, X² represents a —O— group, a —CO—NH— group, a—NH—CO—NH— group, a —OCH₂— group, a —NH—CO— group, a divalent 5-memberedheteroaromatic ring comprising 1, 2, 3 or 4 heteroatoms or a —SO₂—NH—group, n is 0, 1, 2 or 3, m and m′ are independently 0, 1 or 2, Y²represents a hydrogen atom, a hydroxyl group, a morpholinyl group, apiperidinyl group, optionally substituted by a (C₁-C₄)alkyl group, apiperazinyl group, optionally substituted by a (C₁-C₄)alkyl group, or a—CR¹R²R³ group, wherein R¹, R² and R³ independently represent a hydrogenatom, a fluorine atom or a (C₁-C₄)alkyl group, being understood that nomore than one of R¹, R² and R³ is a hydrogen atom, or R¹ and R² formtogether with the carbon atom bearing them a (C₃-C₈)cycloalkyl group,said (C₃-C₈)cycloalkyl group being optionally substituted by one or two(C₁-C₄)alkyl group, halogen atom or (C₁-C₄)alkoxy group and said(C₃-C₈)cycloalkyl group being optionally interrupted on said R¹ and/orR² by an oxygen atom, or alternatively X²—Y² represents a group—C(═O)—NR_(C)R_(d), wherein R_(c) and R_(d) form, together with thenitrogen atom a saturated heterocyclic ring, optionally substituted byone or two (C₁-C₄)alkyl group, by a cyclopentyl group thus forming aspirocyclopentyl derivative, or by a trifluoromethyl group, R and R′independently represent a (C₁-C₄)alkyl group, a (C₃-C₆)cycloalkyl group,a halogen atom, a (C₁-C₅)alkoxy group, a —SO₂—NR_(a)R_(b) group, a —SO₃Hgroup, a —OH group, or a —O—SO₂—OR_(c) group, provided that when X¹ is a—NH—CO— group, Y¹ may further be a phenyl group optionally substitutedby one or two substituent(s) selected from a halogen atom, a(C₁-C₄)alkyl group, a cyano group, a (C₁-C₅)alkoxy group, atrifluoromethyl group, a trifluoromethoxy group, a —SO₂—NR_(a)R_(b)group, a —SO₃H group, a —OH group, a —O—SO₂—OR_(c) group or a—O—P(═O)—(OR_(c))(OR_(d)) group, or any pharmaceutically acceptable saltthereof.
 2. The method according to claim 1, wherein the divalent5-membered heteroaromatic ring comprising 1, 2, 3 or 4 heteroatoms is atriazole or an oxadiazole.
 3. The method according to claim 1, wherein

ring and

ring both represent a phenylene group or

ring represents a pyridylene group and

ring represents a phenylene group.
 4. The method according to claim 1,wherein Y¹ represents a 2-pyridinyl group or a 3-pyridinyl group, apyrimidinyl group or a pyrazinyl group, with one of the nitrogen atomsbeing in ortho position with respect to X₁, provided that when X¹ is a—NH—CO— group, Y¹ may further be a phenyl group.
 5. The method accordingto claim 1, wherein X² represents a —O— group, a —CO—NH— group, adivalent triazole, or a —SO₂—NH— group.
 6. The method according to claim1, wherein Y² represents a hydroxyl group, a morpholinyl group, apiperidinyl group, optionally substituted by a (C₁-C₄)alkyl group, apiperazinyl group, optionally substituted by a (C₁-C₄)alkyl group, or a—CR¹R²R³ group, wherein R¹, R² and R³ independently represent a hydrogenatom, a fluorine atom or a (C₁-C₄)alkyl group, being understood that nomore than one of R¹, R² and R³ is a hydrogen atom, or R¹ and R² formtogether with the carbon atom bearing them a (C₃-C₈)cycloalkyl group. 7.The method according to claim 1, wherein R and R′ independentlyrepresent a (C₁-C₄)alkyl group, a (C₃-C₆)cycloalkyl group, a halogenatom, or a (C₁-C₅)alkoxy group.
 8. The method according to claim 1,wherein

ring and

ring both represent a phenylene group, Y¹ represents a 2-pyridinyl groupprovided that when X¹ is a —NH—CO— group, Y¹ may further be a phenylgroup, X² represents a —O— group, a —CO—NH— group, Y² represents a—CR¹R²R³ group, wherein R¹, R² and R³ independently represent a hydrogenatom, or a (C₁-C₄)alkyl group, being understood that no more than one ofR¹, R² and R³ is a hydrogen atom, or R¹ and R² form together with thecarbon atom bearing them a (C₃-C₈)cycloalkyl group and R³ represents ahydrogen atom or a (C₁-C₄)alkyl group, or a morpholinyl group, and R andR′ independently represent a hydrogen atom, (C₁-C₄)alkyl group, or a(C₃-C₆)cycloalkyl group.
 9. The method according to claim 1, wherein thecompound of formula (I) is a compound of formula (Ia)

wherein Y¹, R, R′, m, m′,

ring, X², n and Y² are as defined in claim 1, or any pharmaceuticallyacceptable salt thereof.
 10. The method according to claim 9, wherein

ring is a phenylene group or a pyridylene group, Y¹ represents a2-pyridyl group, a 3-pyridyl group or a pyrazinyl group, n is 1, 2 or 3,m is 0, R′ is a halogen atom, a (C₁-C₂)alkoxy group or a (C₁-C₂)alkylgroup, X² represents a —CO—NH— group, a —SO₂NH— group or a divalenttriazole, Y² represents a morpholinyl group, a piperidinyl group or apiperazinyl group, optionally substituted by a (C₁-C₄)alkyl group, a—CR¹R²R³ group, wherein R¹, R² and R³ independently represent a hydrogenatom or a (C₁-C₂)alkyl group, being understood that no more than one ofR¹, R² and R³ is a hydrogen atom, or R¹ and R² form together with thecarbon atom bearing them a (C₃-C₆)cycloalkyl group, or alternativelyX²—Y² represents a group —C(═O)—NR_(c)R_(d), wherein R_(c) and R_(d)form, together with the nitrogen atom a saturated heterocyclic ring,optionally substituted by one or two (C₁-C₄)alkyl group, by acyclopentyl group thus forming a spirocyclopentyl derivative, or by atrifluoromethyl group.
 11. The method according to claim 1, wherein thecompound of formula (I) is a compound of formula (Ib)

wherein Y¹, R, R′, m, m′,

ring, X², n and Y² are as defined in claim 1, or any pharmaceuticallyacceptable salt thereof.
 12. The method according to claim 11, wherein

ring is a phenylene group, Y¹ is a phenyl group, a 2-pyridyl group or apyrimidinyl group with one of the nitrogen atom of the pyrimidinyl groupbeing in the ortho position with respect to the —NH— CO-group, n is 1, 2or 3, m is 0, m′ is 0 or 1, R′ is a (C₃-C₆)cycloalkyl group, X²represents a —CO—NH— group, a —O— group or a divalent triazole, Y²represents a hydroxyl group, a morpholinyl group, a piperidinyl group ora piperazinyl group, optionally substituted by a (C₁-C₄)alkyl group, a—CR¹R²R³ group, wherein R¹, R² and R³ independently represent a hydrogenatom or a (C₁-C₂)alkyl group, being understood that no more than one ofR¹, R² and R³ is a hydrogen atom, or R¹ and R² form together with thecarbon atom bearing them a (C₃-C₆)cycloalkyl group, said(C₃-C₆)cycloalkyl group being optionally interrupted on said R¹ and/orR² by an oxygen atom.
 13. The method according to claim 1, wherein thecompound of formula (I) is a compound of formula (Id)

wherein Y¹, R, R′, m, m′,

ring, X², n and Y² are as defined in claim 11, or any pharmaceuticallyacceptable salt thereof.
 14. The method according to claim 13, wherein

ring is a phenylene group, Y¹ represents a 2-pyridyl group or a3-pyridyl group, X² represents a —CO—NH— group, a —SO₂—NH— group or adivalent triazole, m′ and m are 0, n is 1, 2 or 3, Y² represents ahydroxyl or a —CR¹R²R³ group, wherein R¹, R² and R³ independentlyrepresent a hydrogen atom or a (C₁-C₂)alkyl group, being understood thatno more than one of R¹, R² and R³ is a hydrogen atom, or R¹ and R² formtogether with the carbon atom bearing them a (C₃-C₆)cycloalkyl group.15. The method according to claim 1, wherein the compound of formula (I)is selected from (Ia) 1

2

3

4

5

6

7

8

9

10

11

12

13

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

(Ib) 14

15

16

17

18

115

116

117

118

119

120

121

(Id) 32

33

34

35

122

or any pharmaceutically acceptable salt thereof.
 16. The methodaccording to claim 1, wherein the RNA virus infection caused by a RNAvirus belonging to group IV or V of the Baltimore classification isselected from a RSV viral infection, a Chikungunya viral infection, aInfluenza viral infection and a Dengue viral infection.
 17. A compoundof formula (Ia), (Ib), or (Id) or any pharmaceutically acceptable saltthereof:

wherein Y¹ is a 2-pyridyl group, 3-pyridyl or a pyrazinyl group, thegroup

is in meta position on the

ring, with respect to the —NH— group, the

ring is a phenylene group, and with the proviso that compounds 1 and 2are excluded, 1

2

wherein Y¹ is a phenyl group, a 2-pyridyl group or a pyrimidinyl groupwith one of the nitrogen of the pyrimidinyl group being in the orthoposition with respect to the —NH—CO-group,

wherein Y¹ is a 2-pyridyl group, and wherein in each of formula (Ia),(Ib), and (Id); X² independently represents a —O— group, a —CO—NH—group, a —NH—CO—NH— group, —OCH₂— group, a —NH—CO— group, a divalent5-membered heteroaromatic ring comprising 1, 2, 3 or 4 heteroatoms or a—SO₂—NH— group, n is 0, 1, 2 or 3, m and m′ are independently 0, 1 or 2,Y² independently represents a hydrogen atom, a hydroxyl group, amorpholinyl group, a piperidinyl group, optionally substituted by a(C₁-C₄)alkyl group, a piperazinyl group, optionally substituted by a(C₁-C₄)alkyl group, or a —CR¹R²R³ group, wherein R¹, R² and R³independently represent a hydrogen atom, a fluorine atom or a(C₁-C₄)alkyl group, being understood that no more than one of R¹, R² andR³ is a hydrogen atom, or R¹ and R² form together with the carbon atombearing them a (C₃-C₈)cycloalkyl group, said (C₃-C₈)cycloalkyl groupbeing optionally substituted by one or two (C₁-C₄)alkyl group, halogenatom or (C₁-C₄)alkoxy group and said (C₃-C₈)cycloalkyl group beingoptionally interrupted on said R¹ and/or R² by an oxygen atom, oralternatively X²—Y² represents a group —C(═O)—NR_(c)R_(d), wherein R_(c)and R_(d) form, together with the nitrogen atom a saturated heterocyclicring, optionally substituted by one or two (C₁-C₄)alkyl group, by acyclopentyl group thus forming a spirocyclopentyl derivative, or by atrifluoromethyl group, and R and R′ independently represent a(C₁-C₄)alkyl group, a (C₃-C₆)cycloalkyl group, a halogen atom, a(C₁-C₅)alkoxy group, a —SO₂—NR_(a)R_(b) group, a —SO₃H group, a —OHgroup, or a —O—SO₂—OR_(c) group.
 18. The compound according to claim 17,wherein the compound selected from: (Ia) 3

4

5

6

7

8

9

10

11

12

13

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

(Ib) 14

15

16

17

18

115

116

117

118

119

120

121

(Id) 32

33

34

35

122

or a pharmaceutically acceptable salt thereof.
 19. The compoundaccording to claim 18, wherein the pharmaceutically acceptable salt isselected from hydrobromide, tartrate, citrate, trifluoroacetate,ascorbate, hydrochloride, tosylate, triflate, maleate, mesylate,formate, acetate and fumarate.
 20. A pharmaceutical compositioncomprising at least one compound according to claim 18 and also at leastone pharmaceutically acceptable excipient.
 21. A synthesis process formanufacturing the compound according to claim 17, the synthesis processcomprising at least a step of coupling a compound of formula (II)

with a compound of formula (III)

wherein X¹, Y¹, R, R′, m, m′,

ring,

ring, X², Y² are as defined in claim 17 and X is a chlorine atom, aniodine atom or a bromine atom, in presence of an inorganic base and adiphosphine and in the presence of an organometallic catalyst, to obtainthe compound of formula (Ia), (Ib) or (Id).